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CHCHD10-Related Disorders

, PhD, , MD, , PhD, , MD, PhD, and , MD, PhD.

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Summary

Clinical characteristics.

CHCHD10-related disorders are characterized by a spectrum of adult-onset neurologic findings that can include:

  • Mitochondrial myopathy (may also be early-onset): weakness, amyotrophy, exercise intolerance
  • Amyotrophic lateral sclerosis (ALS): progressive degeneration of upper motor neurons (UMNs) and lower motor neurons (LMNs)
  • Frontotemporal dementia (FTD): slowly progressive behavioral changes, language disturbances, cognitive decline, extrapyramidal signs
  • Late-onset spinal motor neuronopathy (SMAJ): weakness, cramps, and/or fasciculations; areflexia
  • Cerebellar ataxia: gait ataxia, kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements), dysarthria/dysphagia, nystagmus, cerebellar oculomotor disorder

Because of the recent discovery of CHCHD10-related disorders and the limited number of affected individuals reported to date, the natural history of these disorders (except for SMAJ caused by the p.Gly66Val pathogenic variant) is largely unknown.

Diagnosis/testing.

The diagnosis is established when a heterozygous CHCHD10 pathogenic variant is detected in an individual with one or more characteristic clinical findings.

Management.

Treatment of manifestations: Adequate nutrition and weight maintenance are essential. Appropriate bracing and stretching can minimize joint contractures, which are often painful and can interfere with caregiving. Those with weakness benefit from assistance with ambulation and posture. Management of ALS, FTD, SMA, and cerebellar ataxia is the same as for other causes of these disorders.

Surveillance: Regular evaluations to detect manifestations that can occur with time including neurologic deficits, psychiatric abnormalities, impaired respiratory function, and sensorineural hearing loss.

Agents/circumstances to avoid: Baclofen (used to treat spasticity) can sometimes worsen muscle weakness; some drugs used to treat the behavioral manifestations of FTD may worsen dysarthria, dysphagia, and/or respiratory weakness.

Genetic counseling.

CHCHD10-related disorders are inherited in an autosomal dominant manner. Many individuals diagnosed with a CHCHD10-related disorder have an affected parent. The proportion of CHCHD10-related disorders caused by a de novo pathogenic variant is unknown. Each child of an individual with a CHCHD10-related disorder has a 50% chance of inheriting the CHCHD10 pathogenic variant. Prenatal testing for pregnancies at increased risk is possible.

GeneReview Scope

CHCHD10-Related Disorders: Included Phenotypes 1
  • Mitochondrial myopathy
  • Amyotrophic lateral sclerosis (ALS)
  • Frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS)
  • Late-onset spinal motor neuronopathy (SMAJ)
1.

For other genetic causes of these phenotypes, see Differential Diagnosis.

Diagnosis

Suggestive Findings

A CHCHD10-related disorder should be suspected in an individual with clinical findings of a mitochondrial myopathy, amyotrophic lateral sclerosis, frontotemporal dementia, or late-onset spinal motor neuronopathy especially when the family history of these diverse phenotypes is consistent with autosomal dominant inheritance (including apparently sporadic cases).

Note: Cerebellar ataxia may be present in combination with mitochondrial myopathy, ALS, and/or FTD.

Clinical Findings

Mitochondrial myopathy

  • Signs of muscle weakness (proximal, axial, and/or facial, including ptosis), amyotrophy, or symptoms that suggest respiratory chain dysfunction, such as exercise intolerance

Amyotrophic lateral sclerosis (ALS)

  • Characteristic signs and symptoms of progressive degeneration of upper motor neurons (UMNs) and lower motor neurons (LMNs)
  • UMN manifestations include stiffness, spasticity, hyperreflexia, Babinski sign, and pseudobulbar palsy (dysphagia and dysarthria)
  • LMN manifestations include weakness accompanied by muscle atrophy, fasciculations, areflexia, and cramping

Note: Most individuals with CHCHD10-related ALS meet El Escorial criteria for ALS [Brooks et al 2000] and have both UMN and LMN involvement. (See also the Amyotrophic Lateral Sclerosis Overview.)

Frontotemporal dementia (FTD)

  • Slowly progressive behavioral changes (disinhibition, loss of initiative, loss of interest in environment, psychiatric symptoms) [Bird et al 1999, Mioshi et al 2010]
  • Language disturbances (word-finding difficulties and semantic paraphasias, perseveration, and echolalia, mutism) [Gorno-Tempini et al 2011]
  • Cognitive decline (executive dysfunctions, attention disorders, and abstract reasoning inability)
  • Extrapyramidal signs (rigidity, bradykinesia)

Late-onset spinal motor neuronopathy (SMN) or spinal muscular atrophy, Jokela type (SMAJ)

  • LMN manifestations including: weakness, cramps, and/or fasciculations that are more proximal than distal; areflexia

Cerebellar ataxia

  • Gait ataxia
  • Kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements)
  • Dysarthria
  • Dysphagia
  • Nystagmus
  • Cerebellar oculomotor disorder

Supportive Laboratory Findings

Although none of the following laboratory findings is specific, all could be considered supportive findings.

Neuroimaging

  • Frontal and/or temporal atrophy on brain CT or MRI [Foster et al 1997, van Swieten et al 1999]
  • Decrease of cerebral perfusion anteriorly (single-photon emission computed tomography [SPECT])
  • Frontotemporal hypometabolism (positron emission tomography with 18F-fluorodeoxyglucose [FDG-PET]) [Foster et al 2007]
  • Reduced striatal uptake of 18F-fluoro-L-dopa [Wszolek et al 1992]

Muscle biopsy findings that support the diagnosis of a mitochondrial myopathy are ragged-red and/or COX negative fibers with or without multiple mtDNA deletions. Note that a muscle biopsy is not required for diagnosis of a CHCHD10-related disorder.

Electromyography and nerve conduction studies (EMG/NCS) demonstrate widespread denervation due to LMN loss in the setting of relatively preserved sensory responses [Gitcho et al 2008, Kühnlein et al 2008].

Serum CK concentration is normal or high.

Establishing the Diagnosis

The diagnosis of a CHCHD10-related disorder is established when a heterozygous pathogenic variant is detected in CHCHD10 (Table 1) in a proband with one or more of the above clinical findings.

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of CHCHD10 is most appropriate in individuals whose family history suggests a CHCHD10-related disorder and in individuals in whom other more common molecular causes of ALS / FTD-ALS / MND (motor neuron disease) have already been ruled out.To date no CHCHD10 deletions/duplications have been reported.
    Targeted analysis for the p.Gly66Val pathogenic variant can be performed first in individuals of Finnish ancestry with late-onset spinal motor neuronopathy (SMN) (SMAJ) [Penttilä et al 2015].
  • A multigene panel that includes CHCHD10 and other genes of interest (see Differential Diagnosis) can also be considered as the initial test. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes CHCHD10) fails to confirm a diagnosis in an individual with features of a CHCHD10-related disorder. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in CHCHD10-related Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
CHCHD10Sequence analysis 2All pathogenic variants reported to date 3
Gene-targeted deletion/duplication analysis 4None reported to date
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Fewer than ten missense variants have been associated with a CHCHD10-related disorder. A founder variant (p.Gly66Val) was identified in 55 individuals from 17 Finnish families [Penttilä et al 2015]. The p.Arg15Leu pathogenic variant was identified in six of 213 families with ALS [Johnson et al 2014, Müller et al 2014, Kurzwelly et al 2015]. Additional missense variants were identified in families [Bannwarth et al 2014, Chaussenot et al 2014, Ajroud-Driss et al 2015, Dobson-Stone et al 2015, Zhang et al 2015] and simplex cases (a single occurrence in a family) [Chaussenot et al 2014, Ronchi et al 2015, Zhang et al 2015].

4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Clinical Characteristics

Clinical Description

The phenotypic spectrum of CHCHD10-related disorders is broad and can include any of the following alone or in any combination: mitochondrial myopathy, amyotrophic lateral sclerosis, frontotemporal dementia, and late-onset spinal motor neuronopathy. Cerebellar ataxia may also be found in combination with these disorders, but not as the sole neurologic manifestation.

CHCHD10 pathogenic variants were originally identified in: (1) a large family with late-onset frontotemporal dementia (FTD), motor neuron disease (MND), cerebellar ataxia, and mitochondrial myopathy with mtDNA deletions [Bannwarth et al 2014] and (2) a large family with early-onset mitochondrial myopathy without mtDNA deletions [Ajroud-Driss et al 2015].

CHCHD10 pathogenic variants have also been described in individuals with frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and familial and sporadic pure ALS [Chaussenot et al 2014, Johnson et al 2014, Müller et al 2014, Kurzwelly et al 2015, Ronchi et al 2015, Zhang et al 2015].

More recently, a CHCHD10 founder variant has been identified in 17 Finnish families with late-onset spinal motor neuronopathy (SMAJ) [Penttilä et al 2015].

Because of the recent discovery of CHCHD10-related disorders and the limited number of affected individuals reported to date, the natural history of these disorders (except for late-onset spinal motor neuronopathy (SMAJ) caused by the p.Gly66Val pathogenic variant) is largely unknown.

Mitochondrial myopathy may present with exercise intolerance; proximal, axial, and/or facial muscle weakness; ptosis; and amyotrophy. Deafness may also be observed.

Amyotrophic lateral sclerosis (ALS). The manifestations of ALS in CHCHD10-related disorders appear to overlap significantly with idiopathic and SOD1-related ALS (see ALS Overview), including gender ratio, age of onset, symptom distribution, and severity of disease. Mean age of onset is 53 years (age range 25-75 years).

Although presentations of ALS of various etiologies may overlap, in CHCHD10-related ALS phenotypes the upper limbs seem to be more frequently involved at the onset and in CHCHD10-related FTD-ALS bulbar involvement is more predominant.

Bulbar dysfunction (atrophy of facial and masticatory muscles, perioral fasciculations, and severe dysphagia leading to frequent aspiration) become prominent in the final stages of the disease. Affected individuals eventually develop respiratory failure, which is the main cause of death.

Intra- and interfamilial variability is observed even with the same CHCHD10 pathogenic variant. Mean disease duration prior to death is 8.6 years (range 2-17 years).

Note: CHCHD10-related ALS is clinically indistinguishable from ALS of other causes. However, based on published data, CHCHD10-related ALS may include upper-limb onset, flail-arm syndrome, and bulbar signs [Müller et al 2014, Bannwarth et al 2015, Kurzwelly et al 2015, Ronchi et al 2015]. Nevertheless, even within a family, clinical variability is considerable, especially regarding age of onset and longevity.

Frontotemporal dementia (FTD) is a presenile dementia affecting the frontal and temporal cortex and some subcortical nuclei. Clinical presentation is variable. Affected individuals may have slowly progressive behavioral changes, language disturbance, and/or extrapyramidal signs. In individuals with CHCHD10-related FTD, symptoms started between ages 50 and 67 years. Disease duration was usually between four and 27 years. The disease progresses over a few years into profound dementia with mutism.

  • Behavioral changes. Disinhibition and loss of initiative are the most common presenting symptoms. Affected individuals lose interest in their environment and neglect their personal hygiene. Obsessive-compulsive behavior and delusions or hallucinations are early clinical features in some. Roaming, restlessness, verbal aggressiveness, hyperorality (including alcohol abuse), and financial mismanagement are frequently seen [Foster et al 1997, Bird et al 1999].
  • Psychiatric manifestations. Persecutory delusions and visual or auditory hallucinations occur rarely in FTD and were not reported in individuals with mutation of CHCHD10.
  • Cognitive decline. Word-finding difficulties and semantic paraphasias in conversational speech are common early findings. Orientation in time and place, visuo-constructive functions, and short-term memory remain intact initially. Executive functions, attention, concentration, and abstract reasoning ability become impaired in all affected individuals. Language comprehension remains relatively preserved over the course of the disease. Perseveration, repetitive utterances, and echolalia lead to mutism after several years [Foster et al 1997].
  • Extrapyramidal signs. Affected individuals may show parkinsonian signs including decreased facial expression, bradykinesia, postural instability, and rigidity without resting tremor. The extrapyramidal signs are unresponsive or only partially responsive to L-dopa treatment.

Spinal motor neuronopathy in CHCHD10-related disorders (SMAJ) is characterized by late onset. Affected individuals develop cramps and fasciculations, slowly progressive and predominantly lower-limb weakness, and diminished or absent deep tendon reflexes; respiratory symptoms are absent. Mild, non-progressive dysphagia appears later in the disease course in 13% of affected individuals. About half of affected individuals develop mild reduction in sensory nerve amplitudes or reduced vibration sense in the distal lower limbs usually later in the disease course. Affected individuals remain ambulant for several decades after onset [Penttilä et al 2015].

Cerebellar ataxia in CHCHD10-related disorders is characterized by ataxia, dysarthria, and eventual deterioration of bulbar functions. Onset is in the sixth decade. Affected individuals have difficulties in gait and slurred speech. They may first notice problems of balance in going down stairs or making sudden turns. In the early stages of disease affected individuals may display brisk deep tendon reflexes, hypermetric saccades, and nystagmus [Schmitz-Hübsch et al 2006]. Mild dysphagia, indicated by choking on food and drink, may also occur early in the disease.

As the disease progresses saccadic velocity slows and up-gaze palsy develops. Nystagmus often disappears with evolving saccadic abnormalities.

As the ataxia worsens, other cerebellar signs such as dysmetria, dysdiadochokinesia, and hypotonia become apparent.

Neuropathology. To date no study of brain pathology has been performed in an individual with a CHCHD10-related disorder.

Genotype-Phenotype Correlations

No obvious genotype-phenotype correlation exists.

The clinical course of CHCHD10-related disorders is highly variable, even within a family, and is not predictable from the type or location of the pathogenic variant.

The same CHCHD10 pathogenic variant can lead to different phenotypes; for example, individuals with the p.Ser59Leu pathogenic variant had different findings including ataxia and/or FTD and/or ALS; the only element common to all affected individuals from the large French family was the laboratory finding of a mitochondrial myopathy with numerous ragged-red and COX-negative fibers associated with multiple mtDNA deletions [Bannwarth et al 2014]. No muscle biopsy was available from the affected individual with the same pathogenic variant reported by Chaussenot et al [2014].

However, it should be noted that:

Penetrance

Penetrance is difficult to estimate because few unaffected individuals in families with a CHCHD10-related disorder have been genotyped or longitudinally followed for the emergence of symptoms.

Complete penetrance was described in all families with a CHCHD10 pathogenic variant [Bannwarth et al 2014, Ajroud-Driss et al 2015, Kurzwelly et al 2015, Penttilä et al 2015] except two families with ALS and the p.Arg15Leu variant [Müller et al 2014] and one with the p.Pro34Ser variant [Dobson-Stone et al 2015]. More reports will be needed before the penetrance can be more accurately established.

Prevalence

The prevalence of CHCHD10-related disorders is not known at present. However, based on the first published series, prevalence of CHCHD10-related disorders is estimated at 1.4%-3.5% in individuals of European ancestry with ALS or the FTD-ALS spectrum [Dobson-Stone et al 2015].

Mutation of CHCHD10 appears to rank immediately following mutation of C9ORF72 and SOD1 as a cause of sporadic ALS [Renton et al 2011].

CHCHD10 pathogenic variants have been identified in individuals from different geographic regions, including America and Europe.

Differential Diagnosis

Mitochondrial myopathy. For a detailed discussion and the differential diagnosis of mitochondrial myopathy, see Mitochondrial Disorders Overview.

Sporadic and familial ALS. For a detailed discussion of these disorders and the differential diagnosis of ALS, see Amyotrophic Lateral Sclerosis Overview.

Familial ALS (FALS) (i.e., presence of at least two affected family members)

Sporadic ALS (SALS) (i.e., single occurrence in a family). Sequencing of CHCHD10 in SALS can be performed.

  • Ronchi et al [2015] also identified the CHCHD10 variants p.Pro34Ser (2 patients) and p.Pro80Leu (1 patient) in Italians with sporadic ALS/FTD-ALS corresponding to 1.4% of Italians with a diagnosis of probable or definite motor neuron disease.
  • In the data sets of Zhang et al [2015] the estimated mutation frequency is 1.2% for sporadic ALS.

Sporadic or familial FTD-ALS (i.e., presence of at least two affected family members)

  • Because FTD/ALS is mainly caused by mutation of C9ORF72, MAPT, FUS1, GRN, TARDBP, and VCP, a tiered approach to testing a proband with autosomal dominant familial FTD-ALS should begin with sequencing of these genes.
  • If no pathogenic variant is identified in C9ORF72, MAPT, FUS1, GRN, TARDBP, or VCP, sequencing of CHCHD10 should then be performed.

CHCHD10-associated ALS must be differentiated from mimics of ALS. Detailed clinical evaluation (as outlined above) usually allows the exclusion of other disorders. The rate of misdiagnosis in ALS is highest in individuals presenting with purely lower motor neuron findings [Traynor et al 2000].

Disorders of any cause that mimic ALS are numerous and include:

See Table 2 for a list of other genes associated with FALS.

Table 2.

Other Genes Associated with FALS

GeneSelected GeneReviewProteinSelected OMIM
ANGALS OverviewAngiogenin611895
DCTN1ALS OverviewDynactin105400
FUS/TLSALS OverviewFused in sarcoma/translated in liposarcoma608030
SETXALS OverviewSenataxin602433
SOD1ALS OverviewSuperoxide dismutase [Cu-Zn]105400
TARDBPTARDBP-Related ALSTAR DNA-binding protein 43612069
VAPBALS OverviewVesicle-associated membrane protein-associated protein B/C608627
VCPInclusion Body Myopathy w/Paget Disease of Bone and/or FTDTransitional endoplasmic reticulum ATPase613954

Pathogenic variants in many of these genes have also been identified in small numbers of simplex cases of ALS (i.e., a single occurrence of ALS in a family).

FTD-ALS. Structural imaging may show focal atrophy and may exclude other causes of dementia (e.g., frontal meningioma, chronic subdural hematoma).

The disorders of any cause that mimic FTD include:

  • Alzheimer disease when individuals present with mild behavioral changes, prominent memory disturbance and loss of initiative, or word-finding problems in the absence of evident frontotemporal atrophy on neuroimaging.
  • Familial Parkinson disease when parkinsonism is present (see Parkinson Disease Overview). Other familial neurologic diseases associated with dementia or parkinsonian features including Huntington disease, dementia with Lewy bodies, and prion diseases also need to be considered.

Non-genetic acquired causes of dementia should always be considered.

About 25% of persons with FTD have a positive family history and demonstrate an autosomal dominant pattern of inheritance.

See Table 3 for a list of other genes associated with FTD-ALS.

Table 3.

Other Genes Associated with FTD-ALS

GeneSelected GeneReviewProteinSelected OMIM
C9orf72C9orf72-Related ALS & FTDUncharacterized protein C9orf72105550
CHMP2BFTD, Chromosome 3-LinkedCharged multivesicular body protein 2b600795
GRN (PGRN)GRN-Related FTDGranulins607485
MAPTMicrotubule-associated protein tau600274
TARDBPTARDBP-Related ALSTAR DNA-binding protein 43612069
VCPInclusion Body Myopathy w/Paget Disease of Bone and/or FTDValosin-containing protein167320

Pathogenic variants in many of these genes have also been identified in small numbers of simplex cases of ALS (i.e., a single occurrence in a family).

FTD = frontotemporal dementia; ALS = amyotrophic lateral sclerosis

Cerebellar ataxia. For a detailed discussion and the differential diagnosis of inherited ataxias myopathy, see Hereditary Ataxia Overview.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a CHCHD10-related disorder, the following evaluations are recommended:

  • A structured general medical history and family history
  • Physical examination and neurologic examination
  • EMG/NCS to document the regions of involvement and indicate lower motor neuron and/or myopathic involvement
  • Evaluation of the extent and profile of cognitive disturbance by neuropsychological examination
  • Neuroimaging with MRI if not done at time of initial diagnosis.
  • Pulmonary function testing to detect and stage respiratory involvement
  • Speech and swallowing evaluation if dysarthria and/or dysphagia are present to direct care to minimize risk of aspiration and to initiate augmentative communication strategies for possible loss of verbal communication
  • Audiologic examination, including auditory brain stem responses (ABRs) and evoked otoacoustic emissions
  • Physical and occupational therapy evaluation to determine the adaptive devices needed to maximize function
  • Nutritional evaluation
  • Screening to detect depression and assess need for psychosocial support
  • Clinical genetics consultation

Treatment of Manifestations

General

  • Adequate nutrition and weight maintenance are essential. Percutaneous gastrostomy is often appropriate to maintain adequate caloric intake in persons with significant bulbar involvement.
  • Joint contractures can occur, are often painful, and can interfere with caregiving. Appropriate bracing and stretching can minimize contractures.

Mitochondrial myopathy

  • Assistance with ambulation and posture
  • Surgical correction of ptosis as needed

Amyotrophic lateral sclerosis (ALS). The management of CHCHD10-related ALS is identical to that of ALS due to other causes, and is outlined in the American Academy of Neurology practice parameter on this topic [Miller et al 1999].

  • Spasticity can be treated with a spasmolytic such as baclofen or a benzodiazepine.
  • Pseudobulbar affect can be treated with a tricyclic antidepressant or combination of quinidine and dextromethorphan.
  • Sialorrhea is often managed with anticholinergic medications (tricyclic antidepressants, scopolamine, atropine drops) or botulinum toxin injection of the salivary glands.
  • Antidepressants are often required to treat concurrent depression.
  • Riluzole is the only FDA-approved treatment for any type of ALS. Although there are no efficacy data specifically for CHCHD10-related ALS, strong consideration should be given to its use.

Frontotemporal dementia (FTD). Treatment follows routine practices.

  • Sedative or antipsychotic drugs help to reduce extreme restlessness, roaming behavior, delusions, and hallucinations.
  • The extrapyramidal signs are usually unresponsive or only partially responsive to L-dopa treatment.
  • Behavioral changes and the loss of insight and judgment in individuals with FTD often present a considerable burden for partners or other caregivers. Information about the disease and psychological support for partners or other caregivers is essential.

Spinal motor neuronopathy. The management of SMAJ is identical to that of adult-onset SMA due to other causes.

Surveillance

The following regular evaluations are indicated to detect manifestations that can occur with time:

  • Neurologic deficits. Neurologic examination including assessment of memory, personality changes
  • Psychiatric abnormalities. Assessment for signs including depression and suicidal ideation
  • Impaired respiratory function. Monitoring of forced vital capacity (FEV) and other aspects of respiratory function performed at clinic visits to determine the appropriate time to offer noninvasive ventilation
  • Sensorineural hearing loss. Audiologic examination including speech discrimination testing

Agents/Circumstances to Avoid

The following should be noted:

  • Baclofen used to treat spasticity can sometimes worsen muscle weakness.
  • Some drugs used to treat the behavioral manifestations of FTD may worsen dysarthria, dysphagia, and/or respiratory weakness.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A clinical trial with the selective serotonin reuptake inhibitor (SSRI) paroxetine showed an increase in cognitive impairment in patients with FTD treated with this drug [Deakin et al 2004]. Conversely, a previous study with another SSRI, trazodone, showed a favorable effect on behavioral disturbances and agitation without cognitive decline [Lebert et al 2004]. Further studies are needed to clarify this issue.

Several trials with memantine are underway in patients with FTD, as well as a trial with oxytocin and its effect on social cognition.

Although no current clinical trials are specifically designed to target CHCHD10-related disorders, many are addressed in the broader category of ALS or FTD.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Mode of Inheritance

CHCHD10-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Many individuals diagnosed with a CHCHD10-related disorder have an affected parent.
  • A proband with CHCHD10-related disorder may have the disorder as the result of de novo CHCHD10 pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are a de novo pathogenic variant in the proband or germline mosaicism in a parent.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include thorough clinical examination and molecular genetic testing for the CHCHD10 pathogenic variant identified in the proband.
  • The family history of some individuals diagnosed with a CHCHD10-related disorder may appear to be negative because of failure by health care professionals to recognize the disorder in family members and/or milder phenotypic presentation, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical and molecular testing has been performed on the parents of the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs of inheriting the CHCHD10 pathogenic variant is 50%.
  • If the CHCHD10 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with a CHCHD10-related disorder has a 50% chance of inheriting the CHCHD10 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has a CHCHD10 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adult relatives of individuals with a CHCHD10-related disorder is possible after molecular genetic testing has identified the specific pathogenic variant in the family. Such testing should be performed in the context of formal genetic counseling. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.

Testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

Testing is appropriate to consider in symptomatic individuals in a family with an established diagnosis of a CHCHD10-related disorder regardless of age.

For more information, see also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the CHCHD10 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for a CHCHD10-related disorder and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for CHCHD10-Related Disorders have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CHCHD10-Related Disorders: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for CHCHD10-Related Disorders (View All in OMIM)

615048SPINAL MUSCULAR ATROPHY, JOKELA TYPE; SMAJ
615903COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 10; CHCHD10
615911FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 2; FTDALS2
616209MYOPATHY, ISOLATED MITOCHONDRIAL, AUTOSOMAL DOMINANT; IMMD

Gene structure. CHCHD10 consists of four exons. Exons 1 and 2 are particularly GC-rich. For a detailed summary of gene and protein information, see Table A, Gene.

Alternative splicing of this gene results in multiple transcripts. The longer transcript variant NM_001301339.1 produces an isoform composed of 149 amino acids (NP_001288268.1) and the transcript variant NM_213720.2 produces a shorter isoform (NP_998885.1) which is composed of 142 amino acids. See also the UniProtKB/Swiss-Prot reference Q8WYQ3

CHCHD10 was previously referred to as C22orf16.

Pathogenic variants. CHCHD10 has only recently been associated with disease. To date all identified CHCHD10 pathogenic variants are located in exon 2. To date no CHCHD10 deletions/duplications have been reported.

The pathogenicity of many of these variants has not been proven by functional studies. In addition, CHCHD10 is often poorly covered in exome data and, therefore, even quite common variants may be absent from databases, complicating the interpretation of variants within this gene.

The CHCHD10 variant p.Arg15Leu was identified in six of 213 families with ALS [Johnson et al 2014, Müller et al 2014, Kurzwelly et al 2015]. Zhang et al [2015] reported this variant in an individual with simplex ALS (i.e., a single occurrence in a family).

The p.Arg15Ser variant was found in cis configuration with p.Gly58Ser in ten individuals in a Puerto Rican family with mitochondrial myopathy without mtDNA deletions [Ajroud-Driss et al 2015].

The p.[Arg15Ser;Gly58Arg] pathogenic variant was identified in a pure early-onset mitochondrial myopathy [Ajroud-Driss et al 2015]. Biochemical analysis showed respiratory chain dysfunction in muscle biopsies from affected individuals. The expression of the p.Gly58Arg, but not p.Arg15Ser, pathogenic variant in transfected cultured cells induced mitochondrial fragmentation. Because the variant is adjacent to p.Ser59Leu, this part of the protein is hypothesized to likely be of importance to mitochondrial function [Penttilä et al 2015].

The p.Ser59Leu pathogenic variant was first identified in a large family in which affected individuals presented with atypical FTD/ALS and mitochondrial myopathy [Bannwarth et al 2014]. In all affected individuals, muscle biopsy showed ragged-red and COX-negative fibers with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Fibroblasts from affected individuals showed respiratory chain deficiency, mitochondrial ultrastructural alterations, and fragmentation of the mitochondrial network [Bannwarth et al 2014]. Overexpression of the CHCHD10 pathogenic variant in HeLa cells led to fragmentation of the mitochondrial network and major ultrastructural abnormalities including loss, disorganization, and dilatation of cristae. As a polar residue of the hydrophobic helix, amino acid Ser59 may intervene in hydrogen bonds to stabilize CHCHD10 interaction with another protein.

The founder variant p.Gly66Val was identified in 55 individuals from 17 Finnish families [Penttilä et al 2015]. The variant p.Gly66Val is a cause of late-onset spinal motor neuronopathy (SMAJ). Because valine is larger in size than glycine, it has been suggested that the bulkier valine molecule could affect the overall structure of the hydrophobic helix [Penttilä et al 2015].

Zhang et al [2015] described the p.Pro80Leu variant in an individual with familial ALS and in an individual with simplex ALS (i.e., a single occurrence in a family). Ronchi et al [2015] described the same variant in two individuals with simplex ALS. Respiratory chain analysis performed on skeletal muscle of an affected individual with early-onset simplex ALS with the CHCHD10 p.Pro80Leu variant revealed combined respiratory chain deficiency and a severe mitochondrial myopathy; further functional analysis would be helpful for validation of its pathogenicity [Ronchi et al 2015]. This variant has also been observed in the general population (exac.broadinstitute.org).

Testing of 115 unrelated individuals with FTD-ALS identified two unrelated individuals with a p.Pro34Ser variant [Chaussenot el al 2014]. Ronchi et al [2015] also identified the same variant in an individual with ALS (of 224 tested). Although the p.Pro34Ser is present in the normal population, it does not segregate with the disease [Dobson-Stone et al 2015, Zhang et al 2015]; however, functional studies favor its pathogenicity [personal data, manuscript submitted].

Table 4.

CHCHD10 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.44G>Tp.Arg15LeuNM_001301339​.1 1
NP_001288268​.1 1
c.67C>Ap.Pro23Thr
c.100C>Tp.Pro34Ser
c.104C>Ap.Ala35Asp
c.176C>Tp.Ser59Leu
c.197G>Tp.Gly66Val
c.239C>Tp.Pro80Leu
c.[43C>G;172G>C]p.[Arg15Ser;Gly58Arg]

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Nucleotide and amino acid changes for pathogenic variants are numbered the same for alternate reference sequences NM_213720​.2, NP_998885​.1.

Normal gene product. CHCHD10, a small mitochondrial protein encoded by the nuclear gene CHCHD10, belongs to a family of mitochondrial proteins characterized by conserved CXnX motifs, some of which are involved in cristae integrity and mitochondrial fusion [Darshi et al 2011, An et al 2012].

CHCHD10 is ubiquitous and highly expressed in organs with high mitochondrial content such as the heart and liver. It is located in the intermembrane space of mitochondria, enriched at cristae junctions and plays a role in the maintenance of mitochondrial network [Ajroud-Driss et al 2015], the morphology of mitochondrial cristae, and the stability of mitochondrial DNA [Bannwarth et al 2014]. CHCHD10 has also been shown to be involved in oxidative phosphorylation, and it possibly takes part in the function of complex IV of the respiratory chain [Martherus et al 2010].

CHCHD10 contains a conserved mitochondrial targeting signal, is highly co-expressed with other mitochondrial genes, and is transcriptionally activated during mitochondrial biogenesis [Ajroud-Driss et al 2015]. The predicted model of CHCHD10 consists of a non-structured N-terminal region, a highly hydrophobic helix (amino acids 43-68), and the CHCH domain near the C-terminal region. The hydrophobic helix may function as an interface of interaction with other proteins and the four cysteine residues (102, 112, 122, 132) of the CHCH domain are involved in two disulfide bonds [Bannwarth et al 2014, Penttilä et al 2015].

Abnormal gene product. Based on current knowledge the ways by which CHCHD10 pathogenic variants could cause disease are by disorganizing mitochondrial cristae, impairing the mitochondrial network, and inducing deficiency in oxidative phosphorylation. Further functional analyses are required for understanding how CHCHD10 pathogenic variants promote motor neuron disease (MND). Although there is no conclusive evidence to date, it appears that CHCHD10 pathogenic variants are likely gain-of-function.

References

Published Guidelines/Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 10-11-18. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2017. Accessed 10-11-18.

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Chapter Notes

Revision History

  • 1 July 2015 (me) Review posted live
  • 20 January 2015 (saem) Original submission
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