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CLPB Deficiency

Synonym: Caseinolytic Peptidase B Deficiency

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

Author Information

Initial Posting: .

Estimated reading time: 14 minutes

Summary

Clinical characteristics.

CLPB (caseinolytic peptidase B) deficiency is characterized by neurologic involvement and neutropenia, which range from severe to mild. To date, a total of 26 individuals from 16 families have been reported.

  • In severe CLPB deficiency, death usually occurs at a few months of age as a result of significant neonatal neurologic involvement (hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy) and severe neutropenia associated with life-threatening infections.
  • In moderate CLPB deficiency neurologic abnormalities in infancy are comparable to but less severe than those observed in the severe phenotype (e.g., hypotonia and feeding problems) and in later childhood can include spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability ranging from mild learning disability to limited development of all cognitive and motor functions. Neutropenia is variable, but not life threatening.
  • In mild CLPB deficiency there is no neurologic involvement, intellect is normal, and neutropenia is mild and intermittent. Life expectancy is normal.

Diagnosis/testing.

The diagnosis of CLPB deficiency is established in a proband with one or more suggestive clinical and/or imaging findings and/or elevated urinary excretion of 3-methylglutaconic acid (3-MGA), and identification of biallelic pathogenic variants in CLPB on molecular genetic testing.

Management.

Treatment of manifestations: Treatment is largely supportive. A multidisciplinary team including a metabolic physician, pediatric neurologist, developmental pediatrician, dietitian, physical therapist, and rehabilitation specialist is recommended. No specific dietary or metabolic treatment is available. Thorough developmental assessment is indicated for all children with cognitive difficulties to tailor special education services. Early intervention may include physical therapy, occupational therapy, and/or speech therapy. Treatment of the neurologic manifestations is per current clinical practice based on the findings. Granulocyte-colony stimulating factor (G-CSF) can be used to increase neutrophil counts to reduce the frequency of infections, especially in individuals with the mild or moderate phenotype.

Surveillance: Neurologic, ophthalmologic, immunologic/hematologic, and orthopedic evaluations are based on individual findings as needed.

Agents/circumstances to avoid: Drugs potentially toxic to mitochondria, including chloramphenicol, aminoglycosides, linezolide, valproic acid, and nucleoside reverse transcriptase inhibitors.

Genetic counseling.

CLPB deficiency is 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. Once the CLPB pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible.

Diagnosis

Suggestive Findings

CLPB (caseinolytic peptidase B) deficiency should be suspected in individuals with the following clinical, laboratory, and imaging findings.

Clinical findings. The disease spectrum of CLPB deficiency ranges from severe to mild. Findings by phenotype:

  • All phenotypes. Congenital or infantile cataracts
  • Severe phenotype
    • Neonates. Hyperekplexia, absence of voluntary movements, respiratory insufficiency, and swallowing problems
    • Neonates or infants. Microcephaly
  • Moderate and severe phenotypes
    • Infants. Ataxia, tremor and dystonia, dyskinesia
    • After infancy. Intellectual ability which can range from normal to severe intellectual disability (with virtually no development), and muscular hypotonia which can progress to spasticity

Laboratory findings

  • Neutropenia beginning at birth can be chronic or intermittent (especially during infections) with absolute neutrophil count (ANC) ranging from severe to mild:
    • Severe. ANC <0.5 per mm3
    • Moderate. ANC <1.0 per mm3
    • Mild. ANC <1.5 per mm3
  • Elevated urinary excretion of 3-methylglutaconic acid (3-MGA) (typically 2-10x the reference range) has been observed in all affected individuals to date.
    Note: (1) Each laboratory has its own reference range; for example, in the authors' laboratory, normal is <20 mmol/mol creatinine. (2) The value can vary between samples from the same individual.

Imaging findings. Initial brain MRI is often unremarkable; however, during infancy progressive cerebral and cerebellar atrophy are seen on follow-up MRI in the majority of affected individuals [Wortmann et al 2015] (full text).

Establishing the Diagnosis

The diagnosis of CLPB deficiency is established in a proband with:

  • One or more suggestive clinical and/or imaging findings;
    AND/OR
  • Elevated urinary excretion of 3-methylglutaconic acid (3-MGA);
    AND
  • Identification of biallelic pathogenic variants in CLPB on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotype of CLPB deficiency is broad, children with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a mild phenotype indistinguishable from many other inherited disorders with intellectual disability and neurologic findings or neutropenia are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of CLPB deficiency, molecular genetic testing approaches can include single-gene testing and use of a multigene panel.

  • Single-gene testing. Sequence analysis of CLPB is performed first. If only one pathogenic variant is found, gene-targeted deletion/duplication analysis could be considered; however, to date no exon or whole-gene deletions have been reported.
  • A multigene panel that includes CLPB and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and 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 provides the best opportunity to identify the genetic cause of condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. (3) 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.

Option 2

When the phenotype is indistinguishable from many other inherited disorders with intellectual disability and neurologic findings or neutropenia, molecular genetic testing approaches can include genomic testing (comprehensive genomic sequencing; recommended) and/or gene-targeted testing (multigene panel; to consider).

Recommended testing. Comprehensive genomic sequencing (when available) including exome sequencing and genome sequencing may be considered if the phenotype alone is insufficient to support gene-targeted testing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Testing to consider. A multigene panel that includes CLPB and other genes of interest (see Differential Diagnosis) may be considered; however, given the rarity of CLPB deficiency many multigene panels for intellectual disability and/or this complex neurologic phenotype or neutropenia may not include this gene.

Table 1.

Molecular Genetic Testing Used in CLPB Deficiency

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
CLPBSequence analysis 316/16 4
Gene-targeted deletion/duplication analysis 5Unknown 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No deletions or duplications involving CLPB have been reported.

Clinical Characteristics

Clinical Description

The disease spectrum of CLPB deficiency ranges from severe to moderate to mild as determined by neurologic involvement and neutropenia. Children with neonatal onset or early-infantile onset have severe involvement and may die from complications of their disease, whereas those with late-infantile and early-childhood onset have a milder clinical presentation [Wortmann et al, unpublished data].

While many, but not all, individuals with CLPB deficiency have bilateral congenital or infantile cataracts, their presence is not associated with the severity of the neurologic involvement or neutropenia.

Although no typical dysmorphic features have been reported, secondary dysmorphic features due to muscle involvement and movement disorder can be seen.

To date a total of 26 individuals from 16 families with CLPB deficiency have been reported in the literature (n=14 [Wortmann et al 2015], n=5 [Saunders et al 2015], n=4 [Capo-Chichi et al 2015], n=2 [Kanabus et al 2015], and n=1 [Kiykim et al 2016]). Most have been identified as neonates; all were symptomatic by early childhood.

Severe Phenotype

Neurologic. Affected infants come to attention at birth with significant neurologic involvement that can include hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, microcephaly (15/23 individuals), and epileptic seizures (with a burst suppression pattern on EEG). All affected infants require neonatal intensive care.

These infants show no motor or intellectual development, and generally die in the first months of life.

Retrospectively, many mothers of infants with the severe phenotype reported issues during the pregnancy, including decreased or increased fetal movements and intrauterine growth restriction [Wortmann et al, unpublished data].

Neutropenia. All infants with the severe phenotype had chronic, severe congenital neutropenia (ANC <500 per mm3) associated with life-threatening infections. Several affected infants progressed to a myelodysplastic syndrome / leukemia-like condition within the first months of life.

Moderate Phenotype

Neurologic. The neonatal course is often complicated by adaptive problems in the broadest sense as well as neurologic abnormalities that are comparable to but less severe than those observed in the severe phenotype (e.g., hypotonia and feeding problems).

Subsequent neurologic involvement varies. In many with neonatal onset generalized hypotonia progresses during childhood to spasticity (mainly of the legs). Many have an infantile-onset progressive movement disorder that can include ataxia, dystonia, or dyskinesia of varying severity. Several have epileptic seizures. All but two have intellectual disability that ranges from mild learning disability to very limited development of all cognitive and motor functions.

Neutropenia with varying ANC is common. Some affected individuals are only neutropenic during infections and some have recurrent (although not life-threatening) infections, including in the neonatal period.

Other. Many show biochemical evidence of endocrine abnormalities (e.g., hypothyroidism).

Mild Phenotype

Mildly affected individuals show only some clinical signs and symptoms without progression and survive without significant disease burden into adulthood.

Neurologic. There is no neurologic involvement; intellect is normal.

Neutropenia is mild and intermittent without increased risk of infection.

Other findings. Nephrocalcinosis and renal cysts without associated medical complications have been described in two individuals with the mild phenotype [Kanabus et al 2015].

Genotype-Phenotype Correlations

The study of genotype-phenotype correlations is hampered by the small number of individuals with CLPB deficiency. The number of patients sharing the same genotype is low.

An overview of all reported affected individuals revealed preliminary evidence in support of a genotype-phenotype correlation: individuals with the most severe phenotypes often have pathogenic variants predicted to lead to the complete absence of functional protein.

Nomenclature

CLPB deficiency may also be referred to as CLPB defect [Wortmann et al 2013a, Capo-Chichi et al 2015, Kanabus et al 2015, Saunders et al 2015, Wortmann et al 2015].

In OMIM 616271, CLPB deficiency is referred to as 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN).

Prevalence

CLPB deficiency is rare. A total of 26 individuals with CLPB deficiency have been reported to date (n=14 [Wortmann et al 2015], n=5 [Saunders et al 2015], n=4 [Capo-Chichi et al 2015], n=2 [Kanabus et al 2015], n=1 [Kiykim et al 2016]). The affected individuals reported are of European, North American, and Asian ancestry.

In the largely Inuit population of Greenland the carrier frequency of the c.803C>T variant was determined to be 3.3%, which is comparable to carrier frequencies of other founder variants in Greenland.

Differential Diagnosis

Table 2. Disorders to Consider in the Differential Diagnosis of CLPB Deficiency

Discriminative FeatureDisorderGene(s)MOIAdditional Hallmarks 1 of the Phenotype
3-MGA-uria 2TAZ defect (Barth syndrome)TAZXLIn affected males: growth delay in infancy, cardiomyopathy (left ventricular non-compaction), neutropenia, myopathy, typical facial features, hypocholesterolemia, & a cognitive phenotype
OPA3 defect (Costeff syndrome; OPA3-related 3-methylglutaconic aciduria)OPA3ARIn infants: optic atrophy & movement disorder (ataxia or extrapyramidal disorder)
SERAC1 defect (MEGDEL syndrome)SERAC1ARNeonatal hypoglycemia & liver failure 3
In 2nd year of life: progressive SNHL & neurologic manifestations (truncal hypotonia, spasticity of the limbs, dystonia, severe ID/DD, Leigh syndrome-like findings on MRI)
TMEM70 defect (OMIM 614052)TMEM70ARTo date no specific syndromic presentation
Typically in neonates: hyperammonemia, lactic acidosis, muscular hypotonia, hypertrophic cardiomyopathy, psychomotor retardation
In individuals surviving neonatal period: DD
DNAJC19 defect (DCMA syndrome) (OMIM 610198)DNAJC5ARCharacteristic combination of childhood-onset dilated cardiomyopathy, non-progressive cerebellar ataxia, testicular dysgenesis, growth failure
AUH defect (3-methylglutaconyl-CoA hydratase deficiency) (OMIM 250950)AUHARAdult-onset progressive spasticity & dementia w/characteristic slowly developing radiologic picture of extensive leukoencephalopathy 4
Uniquely distinguished by elevated urinary excretion of 3-hydroxyisovaleric acid (3-HIVA)
AGK defect (Sengers syndrome) (OMIM 212350)AGKARCharacteristic combination of bilateral cataracts, hypertrophic cardiomyopathy, & no to mild ID
Can be lethal in neonatal period but survivors to adulthood w/mild involvement are known
Not otherwise specified 3-MGA-uria (former 3-MGCA 4)UnknownNormal 3-methylglutaconyl-CoA hydratase enzyme activity & no defect in TAZ, OPA3, SERAC1, TMEM70, DNAJC5, AUH, or AGK
Congenital neutropenia & cyclic neutropeniaELANE-related neutropeniaELANEADIsolated neutropenia; no involvement of the CNS or other organs
G6PC3 deficiencyG6PC3ARPresence of cardiovascular and/or urogenital abnormalities
X-linked congenital neutropenia (see WAS-Related Disorders)WASXLIsolated neutropenia; no involvement of the CNS or other organs
GATA1-related X-linked cytopeniaGATA1XLTypical presentation in affected males: bleeding disorder & anemia; neutropenia occurs later
Shwachman-Diamond syndromeSBDSARIntestinal malabsorption due to exocrine pancreatic dysfunction
HyperekplexiaHereditary hyperekplexiaARHGEF9
GLRA1
GLRB
GPHN
SLC6A5
AD
AR
XL
Generalized stiffness immediately after birth normalizes in 1st years of life.
Unexpected (particularly auditory) stimuli cause excessive startle reflex (eye blinking, flexor spasm of the trunk), followed by a short period of generalized stiffness during which voluntary movements are impossible.
Neutropenia/severe infections, respiratory insufficiency, & swallowing problems are not seen in neonates; affected individuals improve over time.

SNHL = sensorineural hearing loss

ID = intellectual disability

DD = developmental delay

1.

In addition to discriminative feature shown in column 1

2.

Increased urinary excretion of 3-MGA, known as 3-methylglutaconic aciduria (3-MGA-uria), is a relatively common finding in children investigated for suspected inborn errors of metabolism [Wortmann et al 2013b]. The classification of inborn errors of metabolism with 3-MGA-uria as discriminative feature has recently been updated. Click here (pdf) [Wortmann et al 2013a].

3.
4.

Click here (pdf) for information on classification of inborn errors of metabolism in which 3-methylglutaconic aciduria is a discriminative feature.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CLPB deficiency, the following evaluations are recommended:

  • Complete physical examination
  • Complete neurologic examination, including brain MRI (if not performed at the time of diagnosis)
  • Developmental assessment or IQ testing (depending on the age of the individual at the time of diagnosis)
  • For those with significant neurologic problems:
    • Complete evaluation of feeding and diet to determine if tube feeding or gastrostomy is necessary
    • Evaluation of excessive drooling to determine if the risk of aspiration and/or dehydration is increased
  • Complete ophthalmologic examination to evaluate for cataracts (if not performed at the time of diagnosis)
  • Absolute neutrophil count (ANC) is recommended to determine the need for granulocyte-colony stimulating factor (G-CSF) treatment.
  • Ultrasound examination of the kidneys for evidence of nephrocalcinosis or cysts
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment is supportive. Care is best provided by a multidisciplinary team including a metabolic pediatrician, pediatric neurologist, dietitian, and physical therapist when possible.

No specific dietary or other metabolic treatment is available.

Thorough developmental assessment is indicated for all children who exhibit cognitive difficulties in order to determine strengths and weaknesses and to tailor special education services. Early intervention may include physical therapy, occupational therapy, and/or speech therapy.

Treatment of the neurologic manifestations is per current clinical practice based on the findings. To date no specific recommendations regarding the use of antiepileptic drugs are available.

Excessive drooling can be reduced with botulinum toxin injection in the salivary glands, extirpation of saliva glands, and/or re-routing of glandular ducts [SB Wortmann, personal communication].

Granulocyte-colony stimulating factor (G-CSF) administered subcutaneously can be used to increase neutrophil counts to help reduce the frequency of infections, especially in individuals with the mild or moderate phenotype (see Clinical Description) [SB Wortmann, personal communication].

Note: Immunizations are not contraindicated and all children should be immunized as per national standards.

Surveillance

Neurologic, ophthalmologic, immunologic/hematologic, and orthopedic evaluations are based on individual findings as needed.

Agents/Circumstances to Avoid

Drugs potentially toxic to mitochondria (including chloramphenicol, aminoglycosides, linezolide, valproic acid, and nucleoside reverse transcriptase inhibitors) should be avoided.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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

CLPB deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

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

Offspring of a proband. The offspring of an individual with CLPB deficiency are obligate heterozygotes (carriers) for a pathogenic variant in CLPB.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a CLPB pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the CLPB 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 Diagnosis

Once the CLPB pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CLPB deficiency 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.

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.

CLPB Deficiency: 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 CLPB Deficiency (View All in OMIM)

616254CASEINOLYTIC PEPTIDASE B; CLPB
6162713-METHYLGLUTACONIC ACIDURIA WITH CATARACTS, NEUROLOGIC INVOLVEMENT, AND NEUTROPENIA; MEGCANN

Molecular Genetic Pathogenesis

Gene structure. The canonic splice isoform of CLPB, NM_030813.5, consists of 17 exons. Three other isoforms (NM_001258392.2, NM_001258393.2, NM_001258394.2 result in a shorter open reading frame.

NM_001258394.2 has more exons than NM_030813.5 resulting in a longer transcript; however, the resulting protein is shorter and has a different N-terminus because an additional exon in NM_030813.5 (between exons 2 and 3) contains an alternate start codon. Until proven otherwise, molecular genetic testing should include all exons of all isoforms.

Pathogenic variants

Table 4.

Selected CLPB Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequence
c.748C>Tp.Arg250Ter 1NM_030813​.5
c.803C>Tp.Thr268Met 2
c.805G>Ap.Ala269Thr 3
c.815A>Gp.Tyr272Cys 1, 3
c.961A>Tp.Lys321Ter 2
c.1222A>Gp.Arg408Gly 1
c.1233G>Ap.Met411Ile 1
c.1249C>Tp.Arg417Ter 1, 2
c.1305_1307invp.Glu435_Gly436delinsAspPro 1
c.1456T>Cp.Cys486Arg 1
c.1501G>Ap.Glu501Lys 1
c.1685delTp.Ile562ThrfsTer23 4
c.1700A>Gp.Tyr567Cys 1
c.1772C>Tp.Ala591Val 1
c.1850A>Gp.Tyr617Cys 1
c.1882C>Tp.Arg628Cys 5
c.1915G>Ap.Glu639Lys 5
c.1937dupGp.Cys647LeufsTer26 1
c.1937G>Tp.Gly646Val 1
c.2045T>Ap.Ile682Asn 1

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.
2.
3.
4.
5.

Normal gene product. CLPB is a mitochondrial protein of unknown function in human. The bacterial homologue functions as a chaperone facilitating the de- and proper re-folding of misfolded proteins.

CLPB, a member of the large AAA (ATPases associated with diverse cellular activities) protein superfamily, consists of 707 amino acids and contains two main functional domains: the ankyrin domain implicated in a wide range of protein-protein interactions and the ATPase domain. Members of this superfamily are involved in various processes, such as DNA replication and repair and protein disaggregation and refolding, and operate as part of dynein motors, as chelatases or proteases [Snider et al 2008].

Abnormal gene product. Although the function of CLPB is unknown, loss of protein function results in CLPB deficiency.

References

Literature Cited

  • Capo-Chichi JM, Boissel S, Brustein E, Pickles S, Fallet-Bianco C, Nassif C, Patry L, Dobrzeniecka S, Liao M, Labuda D, Samuels ME, Hamdan FF, Vande Velde C, Rouleau GA, Drapeau P, Michaud JL. Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria. J Med Genet. 2015;52:303–11. [PubMed: 25650066]
  • Kanabus M, Shahni R, Saldanha JW, Murphy E, Plagnol V, Hoff WV, Heales S, Rahman S. Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation. J Inherit Metab Dis. 2015;38:211–9. [PubMed: 25595726]
  • Kiykim A, Garncarz W, Karakoc-Aydiner E, Ozen A, Kiykim E, Yesil G, Boztug K, Baris S. Novel CLPB mutation in a patient with 3-methylglutaconic aciduria causing severe neurological involvement and congenital neutropenia. Clin Immunol. 2016;165:1–3. [PubMed: 26916670]
  • Sarig O, Goldsher D, Nousbeck J, Fuchs-Telem D, Cohen-Katsenelson K, Iancu TC, Manov I, Saada A, Sprecher E, Mandel H. Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1. Am J Med Genet A. 2013;161A:2204–15. [PubMed: 23918762]
  • Saunders C, Smith L, Wibrand F, Ravn K, Bross P, Thiffault I, Christensen M, Atherton A, Farrow E, Miller N, Kingsmore SF, Ostergaard E. CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria. Am J Hum Genet. 2015;96:258–65. [PMC free article: PMC4320254] [PubMed: 25597511]
  • Snider J, Thibault G, Houry WA. The AAA+ superfamily of functionally diverse proteins. Genome Biol. 2008;9:216. [PMC free article: PMC2643927] [PubMed: 18466635]
  • Wortmann SB, Duran M, Anikster Y, Barth PG, Sperl W, Zschocke J, Morava E, Wevers RA. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature. J Inherit Metab Dis. 2013a;36:923–8. [PubMed: 23296368]
  • Wortmann SB, Kluijtmans LA, Rodenburg RJ, Sass JO, Nouws J, van Kaauwen EP, Kleefstra T, Tranebjaerg L, de Vries MC, Isohanni P, Walter K, Alkuraya FS, Smuts I, Reinecke CJ, van der Westhuizen FH, Thorburn D, Smeitink JA, Morava E, Wevers RA. 3-Methylglutaconic aciduria --lessons from 50 genes and 977 patients. J Inherit Metab Dis. 2013b;36:913–21. [PubMed: 23355087]
  • Wortmann SB, Kremer BH, Graham A, Willemsen MA, Loupatty FJ, Hogg SL, Engelke UF, Kluijtmans LA, Wanders RJ, Illsinger S, Wilcken B, Cruysberg JR, Das AM, Morava E, Wevers RA. 3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy. Neurology. 2010;75:1079–83. [PubMed: 20855850]
  • Wortmann SB, Ziętkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lücke T, Õunap K, Zordania R, Yaplito-Lee J, van Bokhoven H, Spelbrink JN, Vaz FM, Pras-Raves M, Ploski R, Pronicka E, Klein C, Willemsen MA, de Brouwer AP, Prokisch H, Katsanis N, Wevers RA. CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. Am J Hum Genet. 2015;96:245–57. [PMC free article: PMC4320260] [PubMed: 25597510]

Chapter Notes

Author Notes

Dr SB Wortmann and Prof RA Wevers are interested in patients with elevated urinary excretion of 3-methylglutaconic acid. Combining the clinical, biochemical, and neuroradiologic findings of these patients they are able to define homogeneous subgroups. Next-generation sequencing is then used to identify the underlying genetic disorders in these subgroups, followed by biochemical investigations to characterize the function of the affected protein.

Revision History

  • 22 November 2016 (bp) Review posted live
  • 21 June 2016 (sbw) Original submission
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