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PNPLA6-Related Disorders

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

Author Information

Initial Posting: ; Last Update: June 11, 2015.

Estimated reading time: 22 minutes

Summary

Clinical characteristics.

PNPLA6-related disorders span a phenotypic continuum characterized by variable combinations of cerebellar ataxia, upper motor neuron involvement manifesting as spasticity and/or brisk reflexes, chorioretinal dystrophy associated with variable degrees of reduced visual function, and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics), either in isolation or as part of anterior hypopituitarism (growth hormone, thyroid hormone, or gonadotropin deficiencies). Common but less frequent features are peripheral neuropathy (usually of axonal type manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting), hair anomalies (long eyelashes, bushy eyebrows, or scalp alopecia), short stature, and impaired cognitive functioning (learning disabilities in children and deficits in attention, visuospatial abilities, and recall in adults). Some of these features can occur in distinct clusters on the phenotypic continuum: Boucher-Neuhäuser syndrome (cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism); Gordon Holmes syndrome (cerebellar ataxia, hypogonadotropic hypogonadism, and – to a variable degree – brisk reflexes); Oliver-McFarlane syndrome (trichomegaly, chorioretinal dystrophy, short stature, intellectual disability, and hypopituitarism); Laurence-Moon syndrome; and spastic paraplegia type 39 (SPG39) (upper motor neuron involvement, peripheral neuropathy, and sometimes reduced cognitive functioning and/or cerebellar ataxia).

Diagnosis/testing.

The diagnosis of a PNPLA6-related disorder is suspected on clinical and neuroimaging findings and confirmed by identification of biallelic pathogenic variants in PNPLA6.

Management.

Treatment of manifestations: Management is symptomatic and individually tailored.

  • Ataxia: continuous training of speech and swallowing, fine-motor skills, gait, and balance
  • Spasticity: interventions to improving strength and agility such as exercises, assistive walking devices and/or ankle-foot orthotics, drugs to reduce muscle spasticity
  • Chorioretinal dystrophy: low vision aids when central acuity is reduced; involvement with agencies for the visually impaired re vocational training, mobility training, and skills for independent living
  • Hypothyroidism: hormone replacement therapy as soon as identified
  • Growth hormone deficiency: hormone replacement therapy during childhood and/or adolescence as indicated
  • Hypogonadotropic hypogonadism: hormone replacement therapy at the expected time of puberty

Prevention of secondary complications: A daily regimen of physical therapy to maintain and improve coordination, muscle strength, and gait; to reduce spasticity; and to prevent contractures.

Surveillance: Periodic evaluations (annually or as needed) by a neurologist, ophthalmologist and (if necessary) an endocrinologist to assess progression and develop treatment strategies.

Agents/circumstances to avoid: Alcohol; obesity; inactive, sedentary lifestyle; exposure to medications or chemicals that exacerbate neuropathy.

Genetic counseling.

PNPLA6-related disorders are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the PNPLA6 pathogenic variants in the family have been identified.

GeneReview Scope

PNPLA6-Related Disorders: Included Phenotypes
  • Boucher-Neuhäuser syndrome
  • PNPLA6-related Gordon Holmes syndrome
  • Oliver-McFarlane syndrome
  • PNPLA6-related Laurence-Moon syndrome
  • Spastic paraplegia type 39 (SPG39)

Diagnosis

Due to its highly heterogeneous nature, no formal diagnostic criteria have been established for PNPLA6-related disorders based on clinical findings alone. The diagnosis can only be established by molecular genetic testing.

Suggestive Findings

A PNPLA6-related disorder should be suspected in individuals with a combination of two or more of the following clinical features:

  • Cerebellar ataxia starting before age 50 years and associated with cerebellar atrophy
  • Upper motor neuron involvement presenting as spasticity and/or brisk reflexes
  • Chorioretinal dystrophy starting before age 50 years and leading to variable degrees of reduced visual function, including blindness. The diagnosis of chorioretinal dystrophy may be established by ophthalmologic assessment, including visual acuity, visual field testing, fundoscopy, and optic coherence tomography (OCT) [Synofzik et al 2015]. OCT can detect thinning of the retina, loss of layered retinal architecture, and effacement of the choriocapillaris and choroidal vessels. Autofluorescence photographs and fluorescein angiography provide supplementary diagnostic information by revealing hyper- and hypofluorescent regions of abnormal retinal pigment epithelium and the choriocapillaris.
  • Hypogonadotropic hypogonadism usually presenting in the first two decades of life

Common, but less frequent features:

  • Anterior hypopituitarism. Deficiency of hormones made by the anterior pituitary can result in growth hormone deficiency and insufficient production of thyroid or sex hormones. Deficient thyroid hormone production can result in intellectual disability in infancy and childhood and poor growth in infancy, childhood, and adolescence. Growth hormone deficiency can lead to short stature in infancy, childhood, or adolescence. Insufficient sex hormone production can lead to hypogonadotropic hypogonadism (see above).
  • Peripheral neuropathy (usually of axonal type), presenting with reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting
  • Impaired cognitive functioning unrelated to hormone deficiency that can include learning disabilities in children [Yoon et al 2013] and deficits in attention, visuospatial abilities, and recall in adults
  • Hair anomalies (long eyelashes, bushy eyebrows, or scalp alopecia)

Some of these features can occur in certain combinations, presenting in partly distinct/partly overlapping clusters on the phenotypic continuum of the PNPLA6-related disorders:

  • Boucher-Neuhäuser syndrome. Cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism [Boucher & Gibberd 1969]; high predictive value (75%) for an underlying PNPLA6-related disorder [Synofzik et al 2014a, Tarnutzer et al 2015]
  • Gordon Holmes syndrome. Cerebellar ataxia, hypogonadotropic hypogonadism, and (to a variable degree) brisk reflexes [Holmes 1907]
  • Oliver-McFarlane syndrome. Trichomegaly, chorioretinal dystrophy, and congenital or childhood hypopituitarism [Hufnagel et al 2015, Kmoch et al 2015]
  • Laurence-Moon syndrome. Cerebellar ataxia, chorioretinal dystrophy, peripheral neuropathy, spastic paraplegia and congenital or childhood hypopituitarism. One family diagnosed with Laurence-Moon syndrome has been reported to have biallelic pathogenic variants in PNPLA6 [Hufnagel et al 2015]. Several other people with the same phenotypic cluster and biallelic pathogenic variants in PNPLA6 have been reported [Synofzik et al 2014a] and described to have "spastic Boucher-Neuhäuser syndrome," demonstrating the continuum of PNPLA6- associated phenotypic clusters.
  • Spastic paraplegia type 39 (SPG39). Upper motor neuron involvement and peripheral neuropathy, and sometimes reduced cognitive functioning and/or cerebellar ataxia [Rainier et al 2008]
  • Severe retinal dystrophy with atrophy associated with autism, reported in one child with biallelic pathogenic variants in PNPLA6 [Kmoch et al 2015]. The child had been previously given a diagnosis of Leber congenital amaurosis (LCA). Given the age of the affected individual, it is possible that further features of one of the above clinical diagnoses could develop with time. See Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview.

The full phenotypic spectrum of PNPLA6-related disorders and the predictive value of the clinical features for identifying an underlying PNPLA6-related disorder remain to be confirmed.

Establishing the Diagnosis

The diagnosis of a PNPLA6-related disorder is established in a proband by detection of biallelic PNPLA6 pathogenic variants in trans configuration (see Table 1).

One genetic testing strategy is sequence analysis of PNPLA6, followed by deletion/duplication analysis if only one or no pathogenic variant is identified. One exon duplication has been reported to date [Hufnagel et al 2015].

An alternative genetic testing strategy is use of a multigene sequencing panel that includes PNPLA6 and other genes of interest (see Differential Diagnosis). 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.

Table 1.

Molecular Genetic Testing Used in PNPLA6-Related Disorders

Gene 1MethodProportion of Probands with a Pathogenic Variant Detectable by Method
PNPLA6Sequence analysis 2>20 families reported to date
Deletion/duplication analysis 31 reported to date 4
1.

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

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.

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

4.

An intragenic duplication of exons 14-20 in PNPLA6 has been reported in one individual with Oliver-McFarlane syndrome [Hufnagel et al 2015].

Clinical Characteristics

Clinical Description

In all affected individuals reported to date, features of the PNPLA6-related disorder manifested in the first two decades of life [Rainier et al 2011, Yoon et al 2013, Deik et al 2014, Synofzik et al 2014a, Hufnagel et al 2015, Kmoch et al 2015, Tarnutzer et al 2015]. The initial findings include one or several of the following features: gait disturbance, visual impairment due to chorioretinal dystrophy or atrophy, anterior hypopituitarism, or delayed puberty/primary amenorrhea. Gait disturbance may precede visual impairment or anterior hypopituitarism; or, in contrast, gait disturbance may follow visual impairment or hypopituitarism up to 35 years later [Deik et al 2014]. Although the combination of the three most common findings (gait disturbance, visual impairment, and delayed puberty/primary amenorrhea) is highly indicative of an underlying PNPLA6-related disorder, no single feature is specific or obligatory.

Given the limited number of individuals reported to date and the lack of longitudinal studies of affected individuals, a more detailed understanding of the natural history of PNPLA6-related disorders remains to be determined.

Gait disturbance is due to ataxia, spasticity (with or without paresis), peripheral neuropathy, or a combination thereof. Progression of the gait disturbance varies: more severely affected individuals lose the ability to walk without aid between ages 25 and 50 years and may become wheelchair dependent at this stage [Rainier et al 2011, Synofzik et al 2014a]; less affected individuals are still able to walk unaided at age 54 years [Synofzik et al 2014a].

Peripheral neuropathy, if present, is usually of the axonal motor type, including an additional sensory component (sensorimotor neuropathy) reported to date in only three cases [Author, unpublished observation]. The motor neuropathy can be associated with severe atrophy of distal muscles, in particular the distal leg and intrinsic hand muscles, starting in the late teens [Rainier et al 2011]. Impairment of the sensory tracts (peripheral sensory neurons, dorsal columns) including diminished vibration sense and touch has been reported in different age groups [Rainier et al 2011, Synofzik et al 2014a, Hufnagel et al 2015, Kmoch et al 2015].

Functional impairment due to upper motor neuron involvement varies: while some affected individuals show only increased reflexes or extensor plantar responses, others have severe spastic paraparesis of the lower extremities [Rainier et al 2011, Synofzik et al 2014a, Hufnagel et al 2015]. Electrophysiologic data available are currently insufficient to determine whether corticospinal tract involvement is axonal (with motor evoked potentials showing almost normal central motor conduction times) or demyelinating (with motor evoked potentials showing severely prolonged central motor conduction times).

Progressive visual impairment, which is less frequent than gait disturbances in the PNPLA6-related disorders, is typically due to chorioretinal dystrophy that is usually characterized by diffuse atrophy of choroidal vessels and retinal pigment epithelium on fundoscopy, leading to complete loss of the choriocapillaris layer and the retinal pigment epithelium [Deik et al 2014, Synofzik et al 2015], including death of photoreceptors and retinal thinning accompanied by lipofuscin metabolism abnormalities [Kmoch et al 2015]. Initially these deficits can present in the first few years of life with nystagmus, choroidal and retinal pigment atrophy, and bitemporal central visual field defects and blind spot enlargement. Visual acuity is often severely reduced (to perception of hand motion) such that some affected individuals meet the criteria for legal blindness in adolescence or adulthood [Synofzik et al 2014a, Synofzik et al 2015, Hufnagel et al 2015, Kmoch et al 2015].

Anterior hypopituitarism manifests either in infancy or childhood (micropenis, cryptorchidism, thyroid and growth hormone deficiency) or in adolescence (hypogonadotropic hypogonadism and growth hormone deficiency) [Hufnagel et al 2015]. Congenital hypothyroidism and growth hormone deficiency can result in global developmental delay, severe cognitive impairment, and short stature. Hypogonadotropic hypogonadism usually becomes manifest during the second decade of life with delayed puberty and lack of secondary sexual characteristics including primary amenorrhea, small penis and testes, and absent pubic hair and/or breast development. These hormone deficiencies are responsive to hormone replacement therapy.

Cognitive functioning appears to be impaired in many (albeit not all) individuals with a PNPLA6-related disorder, including learning disabilities in children [Yoon et al 2013] and deficits in attention, visuospatial abilities, and recall in adults. Cognitive disability may be related to hypothyroidism in certain but not all individuals with biallelic pathogenic variants in PNPLA6.

Neuroimaging has shown the following:

Genotype-Phenotype Correlations

No obvious genotype-phenotype correlation exists. It has been suggested that different biallelic pathogenic variants could lead to different dose-dependent reductions in hydrolysis activity of the neuropathy target esterase (NTE), with more severe reductions leading to more severe and early-onset phenotypes [Hufnagel et al 2015]. However, this hypothesis warrants further confirmation from larger genotype-phenotype studies, in particular given the fact that the same PNPLA6 pathogenic variant can lead to different presentations (e.g., ataxia plus hypogonadism in one individual, and spastic ataxia in another) and to different degrees and progression rates of manifestation (e.g., loss of ambulation in a 44-year-old with a 17-year history of ataxia vs. full ambulation in a 42-year-old with a 36-year history of ataxia) [Synofzik et al 2014a]. Correspondingly, manifestations and disease progression differ not only between but also within families.

Nor does the phenotype appear to depend on either the location of the pathogenic variant (e.g., mutation of the functionally important phospholipid esterase domain can present with a severe Oliver-McFarlane or Boucher-Neuhäuser syndrome as well as with relatively mild spastic paraplegia; pathogenic variants occurring outside the esterase domain have been associated with Boucher-Neuhäuser syndrome, Oliver-McFarlane syndrome, and severe retinal dystrophy with atrophy and autism) or the pathogenic variant type (e.g., both missense and frameshift variants have been reported with severe Oliver-McFarlane or Boucher-Neuhäuser syndrome as well as with mild spastic ataxia) [Synofzik et al 2014a, Hufnagel et al 2015, Kmoch et al 2015].

Penetrance

Penetrance appears to be complete in individuals with biallelic PNPLA6 pathogenic variants.

Prevalence

PNPLA6-related disorders are rare in unselected neurologic populations. Synofzik et al [2014a] identified two affected persons in 538 unrelated individuals with ataxia, spastic paraplegia, and/or neuropathy.

In contrast, mutation of PNPLA6 is common in Boucher-Neuhäuser syndrome and Oliver-McFarlane syndrome: individuals in four of six families with Boucher-Neuhäuser syndrome and 11 of 12 families with Oliver-McFarlane syndrome had biallelic pathogenic variants in PNPLA6 [Synofzik et al 2014a, Hufnagel et al 2015, Kmoch et al 2015]. Given that clinical descriptions of more than 30 index cases with Boucher-Neuhäuser or Oliver-McFarlane syndromes have been reported to date, the number of individuals with this phenotype who are found to have biallelic PNPLA6 pathogenic variants is likely to increase soon.

Differential Diagnosis

Disorders with Ataxia

Ataxia with hypogonadism and dementia. In contrast to RNF216/OTUD4-associated ataxia-hypogonadism, PNPLA6-related disorders are not typically accompanied by dementia. Biallelic mutation of RNF216 or, in one family, biallelic pathogenic variants in both RNF216 and OTUD4, are causative [Margolin et al 2013].

Autosomal recessive spinocerebellar ataxia 16 (SCAR16) is characterized by ataxia with cerebellar atrophy and, to a variable degree, cognitive impairment, hypogonadism, and/or pyramidal tract involvement [Shi et al 2014, Synofzik et al 2014b]. While phenotypic overlap exists, PNPLA6-related disorders are characterized by more rapid disease progression, and (unlike SCAR16), they include chorioretinal dystrophy. Biallelic pathogenic variants in STUB1 (CHIP) are causative. See Hereditary Ataxia Overview.

Ataxia with hypogonadotropic hypogonadism, dental abnormalities and hypomyelinating leukodystrophy. In contrast to this disorder, PNPLA6-related disorders are not associated with dental abnormalities or leukodystrophy. Biallelic pathogenic variants in POLR3A or POLR3B are causative [Daoud et al 2013, Synofzik et al 2013a].

Marinesco-Sjögren syndrome is characterized by cerebellar ataxia with cerebellar atrophy, early-onset cataracts, mild to severe intellectual disability, hypotonia, muscle weakness, and hypergonadotropic hypogonadism due to biallelic pathogenic variants in SIL1. Marinesco-Sjögren syndrome is invariably associated with the combination of a cerebellar syndrome, chronic myopathy, and cataracts after age seven years [Krieger et al 2013]; myopathy and cataracts have not been reported in PNPLA6-related disorders. Biallelic mutation of SIL1 is causative.

Ataxia with hypergonadotropic hypogonadism due to coenzyme Q10 deficiency. In contrast to coenzyme Q10 deficiency, PNPLA6-related disorders may present with hypogonadotropic hypogonadism, and are not known to be associated with CoQ10 deficiency. See Hereditary Ataxia Overview.

Infantile-onset spinocerebellar ataxia (IOSCA) is a severe, progressive neurodegenerative disorder characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis. By adolescence, hypergonadotropic hypogonadism in females becomes evident. In contrast to PNPLA6-related disorders, IOSCA usually starts in early childhood and is mostly accompanied by athetosis, deafness, ophthalmoplegia, and/or epilepsy. Biallelic pathogenic variants in TWNK (previously C10orf2) are causative.

Abetalipoproteinemia (Bassen-Kornzweig syndrome) and familial hypobetalipoproteinemia (OMIM 615558, 605019) present with retinitis pigmentosa, progressive ataxia, steatorrhea, demyelinating neuropathy, dystonia, extrapyramidal signs, and spastic paraparesis (rare). Hypocholesterolemia and reduced lipid-soluble vitamins in serum are due to defective intestinal absorption of lipids. Biallelic pathogenic variants in MTP are causative of abetalipoproteinemia. Mutation of APOB or ANGPTL3 causes familial hypobetalipoproteinemia.

Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) is a childhood-onset disease most often characterized by proximal neurogenic muscle weakness with sensory neuropathy, ataxia, learning difficulties, and pigmentary retinopathy. Mutation of the mitochondrial DNA gene MT-ATP6 is causative.

Refsum disease is characterized by anosmia (a universal finding) and early-onset retinitis pigmentosa with variable combinations of chronic polyneuropathy, deafness, cerebellar ataxia, and ichthyosis. Cardiac conduction disorders are common. Serum concentration of phytanic acids is increased as their degradation is impeded by the underlying genetic defect. Biallelic pathogenic variants in PHYH or PEX7 are causative.

Spinocerebellar ataxia type 7 is characterized by progressive cerebellar ataxia, including dysarthria and dysphagia, and a cone-rod retinal dystrophy with progressive central visual loss resulting in blindness in affected adults. Onset in early childhood or infancy has an especially rapid and aggressive course often associated with failure to thrive and regression of motor milestones. Expansion of a CAG trinucleotide repeat in ATXN7 is causative.

Ataxia with vitamin E deficiency (AVED) presents with early-onset progressive ataxia, clumsiness of the hands, loss of proprioception (especially of vibration and joint position sense), and areflexia. The principal criterion for diagnosis of AVED is a Friedreich ataxia-like neurologic phenotype combined with markedly reduced plasma vitamin E (α-tocopherol) concentration in the absence of known causes of malabsorption. Biallelic pathogenic variants in TTPA are causative.

Troyer syndrome is characterized by progressive spastic paraparesis, dysarthria, pseudobulbar palsy, distal amyotrophy, motor and cognitive delays, short stature, and subtle skeletal abnormalities. Biallelic pathogenic variants in SPART are causative.

See also Hereditary Ataxia Overview.

Chorioretinal Dystrophy

Leber congenital amaurosis (LCA), a severe dystrophy of the retina, typically becomes evident in the first year of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus. Visual acuity is rarely better than 20/400. A characteristic finding is Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing. The appearance of the fundus is extremely variable. While the retina may initially appear normal, a pigmentary retinopathy reminiscent of retinitis pigmentosa is frequently observed later in childhood. The electroretinogram (ERG) is characteristically "nondetectable" or severely subnormal. Pathogenic variants in 17 genes are known to cause LCA: GUCY2D (locus: LCA1), RPE65 (LCA2), SPATA7 (LCA3), AIPL1 (LCA4), LCA5 (LCA5), RPGRIP1 (LCA6), CRX (LCA7), CRB1 (LCA8), NMNAT1 (LCA9), CEP290 (LCA10), IMPDH1 (LCA11), RD3 (LCA12), RDH12 (LCA13), LRAT (LCA14), TULP1 (LCA15), KCNJ13 (LCA16), and IQCB1. Together, pathogenic variants in these genes are estimated to account for more than half of all LCA diagnoses. LCA is most often inherited in an autosomal recessive manner, with the exception of LCA caused by heterozygous pathogenic variants in CRX, which is inherited in an autosomal dominant manner.

See also Retinitis Pigmentosa Overview.

Other Types of Disorders

Multisystem mitochondrial diseases with retinopathy. See Mitochondrial Disorders Overview.

Peripheral neuropathies with additional multisystem disease, including retinopathies. See Charcot-Marie-Tooth Hereditary Neuropathy Overview.

Complicated hereditary spastic paraplegias. See Hereditary Spastic Paraplegia Overview.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a PNPLA6-related disorder, the following evaluations are recommended:

  • MRI of the cerebrum (including the pituitary), cerebellum, and spinal cord (including the thoracic cord) to establish the extent of atrophy in the different brain regions and exclude other secondary causes for the clinical features
  • Nerve conduction studies and EMG to determine the presence and extent of peripheral neuropathy
  • Neuropsychological investigation, including IQ, attention span, visuospatial abilities, and recall
  • If not performed at the time of diagnosis, ophthalmologic assessment, including visual acuity, visual field testing, fundoscopy, and optic coherence tomography (OCT) [Synofzik et al 2015]. OCT can detect thinning of the retina, loss of layered retinal architecture, and effacement of the choriocapillaris and choroidal vessels. Autofluorescence photographs and fluorescein angiography provide supplementary diagnostic information by revealing hyper- and hypofluorescent regions of abnormal retinal pigment epithelium and the choriocapillaris.
  • If not performed at the time of diagnosis, endocrinologic assessment for evidence of hypothyroidism, growth hormone deficiency, and hypogonadotropic hypogonadism. Hypogonadotropic hypogonadism is detected by decreased rise of gonadotropin levels (LH, FSH) in response to gonadotropin releasing hormone (GnRH). (See Isolated Gonadotropin-Releasing Hormone Deficiency for more details about evaluation.)
  • Clinical genetics consultation

Treatment of Manifestations

No disease-modifying drug treatment exists for PNPLA6-related disorders. Given the great phenotypic variability and broad spectrum of the disorders, management of symptoms must be individually tailored.

Ataxia. Management should be directed to providing continuous training in the form of active speech, fine-motor, and gait exercises [Fonteyn et al 2014, Ilg et al 2014, Synofzik & Ilg 2014]:

Spasticity. Management should be directed to improving balance, strength, and agility:

  • Daily regimen with physiotherapy exercises focusing on improving muscle strength and gait and reducing spasticity
  • Assistive walking devices and ankle-foot orthotics
  • Drugs to reduce muscle spasticity (e.g., baclofen [oral or intrathecal], tolperison; Botox® injections) and urinary urgency (e.g., oxybutynin)

Visual impairment. Low vision aids such as magnifiers may facilitate reading for individuals with reduced central acuity.

In the US, publicly funded agencies for the visually impaired at the state level provide services for the blind or those with progressive eye disorders; services include vocational training, mobility training, and skills for independent living.

Hypothyroidism. Hypothyroidism is treated with thyroid hormone replacement (e.g., levothyroxine) at the time of diagnosis. Thyroid hormone levels should be normalized by replacement therapy and monitored by an endocrinologist.

Growth hormone deficiency. Growth hormone deficiency is treated with hormone replacement therapy and monitored by an endocrinologist.

Hypogonadism. Hypogonadotropic hypogonadism is treated with hormone replacement therapy, often including gonadotropins, at the expected time of puberty. (See Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency) for more details about treatment.)

Prevention of Secondary Complications

Daily physical therapy is recommended to maintain and improve coordination, muscle strength, and gait; reduce spasticity; and prevent contractures.

Surveillance

Patients should be evaluated periodically (annually or as needed) by a neurologist, ophthalmologist and, if necessary, endocrinologist to assess progression and develop treatment strategies.

Agents/Circumstances to Avoid

Avoid the following:

  • Alcohol
  • Obesity
  • Inactive, sedentary lifestyle
  • Exposure to medications or chemicals that exacerbate neuropathy. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list of medications that are potentially toxic to persons with CMT or a related neuropathy.

Evaluation of Relatives at Risk

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

Pregnancy Management

Anecdotally, ataxia may sometimes appear for the first time or worsen during pregnancy. Note: While some individuals with ataxia report a worsening of coordination after general anesthesia, no increased risk has been reported specifically with obstetric anesthesia.

Spasticity generally does not change significantly with pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

PNPLA6-related disorders are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one PNPLA6 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Although affected sibs usually share most of the same PNPLA6-related phenotypic features, some features may be missing or additionally present. For example, within the same family, one sib may have all features of Boucher-Neuhäuser syndrome and another sib may have either spastic ataxia with hypogonadism or chorioretinal dystrophy, but not both. The degree and progression of impairment may also differ between sibs.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with a PNPLA6-related disorder are obligate heterozygotes (carriers of a pathogenic variant in PNPLA6).

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Heterozygote (Carrier) Detection

Carrier testing for at-risk relatives requires prior identification of the PNPLA6 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

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 Testing

Once the PNPLA6 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for a PNPLA6-related disorder are possible. However, given the possibility of intrafamilial variability, the results of such testing do not necessarily predict the phenotype, age of onset, and/or severity of findings.

Prenatal testing requests vary in frequency for conditions which (like PNPLA6-related disorders) have no disease-modifying treatment and can present with a wide spectrum of phenotypic features. Requests may be more common in families in which affected individuals have had early-onset disease affecting many neurologic systems as well as intellect. 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.

  • Ataxia UK
    Lincoln House
    1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: 0845 644 0606 (helpline); 020 7582 1444 (office); +44 (0) 20 7582 1444 (from abroad)
    Email: helpline@ataxia.org.uk; office@ataxia.org.uk
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • Spastic Paraplegia Foundation, Inc.
    7700 Leesburg Pike
    Ste 123
    Falls Church VA 22043
    Phone: 877-773-4483 (toll-free)
    Email: information@sp-foundation.org

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.

PNPLA6-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 PNPLA6-Related Disorders (View All in OMIM)

212840GORDON HOLMES SYNDROME; GDHS
215470BOUCHER-NEUHAUSER SYNDROME; BNHS
245800LAURENCE-MOON SYNDROME; LNMS
275400OLIVER-MCFARLANE SYNDROME; OMCS
603197PATATIN-LIKE PHOSPHOLIPASE DOMAIN-CONTAINING PROTEIN 6; PNPLA6
612020SPASTIC PARAPLEGIA 39, AUTOSOMAL RECESSIVE; SPG39

Gene structure. PNPLA6 comprises 34 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The large majority of PNPLA6 pathogenic variants identified to date cluster within a short stretch of about 300 nucleotides that encode the roughly 100 residues in the functionally critical EST domain [Synofzik et al 2014a].

Several reported PNPLA6 pathogenic variants are located in the region encoding the CNB1 and CNB2 domains (e.g., c.787G>A and c.1732G>T). These and other variants in the CNB domains likely compromise the ability of one or both regulatory CNB1/2 domains to bind cyclic nucleotide-monophosphate binding domains (cNMPs); thus, their failure to undergo a conformational change in response to changes in intracellular concentration of cNMPs would keep the esterase (EST) domain in an auto-inhibited state [Synofzik et al 2014a, Hufnagel et al 2015, Kmoch et al 2015].

Table 2.

PNPLA6 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.787G>Ap.Val263IleNM_001166111​.1
NP_001159583​.1
c.1732G>Tp.Gly578Trp

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

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

Normal gene product. PNPLA6 encodes the neuropathy target esterase, which belongs to a protein family of nine patatin-like phospholipase domain-containing proteins. Apart from its phospholipid esterase domain (EST; also sometimes called "patatin domain"), the modular architecture of PNPLA6 protein contains three CNB domains (CNB1, CNB2, CNB3).

The most important functional domain is the EST domain, which de-esterifies phosphatidylcholine (a major component of biologic membranes) into its constituent fatty acids and glycerophosphocholine [Strickland et al 1995, Atkins et al 2002, van Tienhoven et al 2002, Zaccheo et al 2004]. Glycerophosphocholine serves as a precursor for the biosynthesis of acetylcholine, a key neurotransmitter involved in mediating cellular signaling in the nervous system. Moreover, it has been suggested that the EST domain has a role in lysophospholipase activity [van Tienhoven et al 2002] and functions in lipid membrane metabolism [Tesson et al 2012].

Abnormal gene product. Current knowledge suggests that PNPLA6 pathogenic variants cause disease by impairing the capacity of the EST domain to perform ONE of two functions:

  • De-esterify phosphatidylcholine into fatty acids and glycerophosphocholine (The lack of adequate glycerophosphocholine may disturb development and maintenance of synaptic connections in a variety of neuronal networks.)
  • Catalyze 2-arachidonoyl lysophosphatidylinositol, thus disturbing the metabolism of lipid membranes [Synofzik et al 2014a, Hufnagel et al 2015, Kmoch et al 2015]

The EST domain is altered not only by mutation but also by the toxic effects of organophosphorous compounds [Rainier et al 2008, Richardson et al 2013] that are used in industry, agriculture, suicide attempts, chemical warfare, terrorist incidents (1995 Tokyo subway incident), and modification of alcoholic beverages (Jamaica "Ginger Jake" during the Prohibition era) [Richardson et al 2013].

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Chapter Notes

Acknowledgments

This work was supported by the Interdisciplinary Center for Clinical Research IZKF Tübingen (Grant 2191-0-0 to MS), U54NS0657, R01NS075764, R01NS072248, the MDA, and the CMT Association.

Revision History

  • 11 June 2015 (me) Comprehensive update posted live
  • 9 October 2014 (me) Review posted live
  • 29 May 2014 (ms) Original submission
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