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Hypomyelination and Congenital Cataract

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

Author Information
, MD, PhD
Department of Neuroscience
G Gaslini Pediatric Institute and University of Genova
Genova, Italy
, PhD
Department of Neuroscience
G Gaslini Pediatric Institute and University of Genova
Genova, Italy
, MD, PhD
Department of Neuroscience
G Gaslini Pediatric Institute and University of Genova
Genova, Italy
, MD
Department of Neuroscience
G Gaslini Pediatric Institute and University of Genova
Genova, Italy
, MD
Department of Neuroradiology
G Gaslini Pediatric Institute and University of Genova
Genova, Italy
, MD, PhD
Professor, Department of Child Neurology
Vrije Universiteit Medical Center
Amsterdam, The Netherlands
, MD
Department of Neuroscience
G Gaslini Pediatric Institute and University of Genova
Genova, Italy

Initial Posting: ; Last Revision: October 27, 2011.

Summary

Disease characteristics. Hypomyelination and congenital cataract (HCC) is usually characterized by bilateral congenital cataracts and normal psychomotor development in the first year of life, followed by slowly progressive neurologic impairment manifest as ataxia, spasticity (brisk tendon reflexes and bilateral extensor plantar responses), and mild to moderate cognitive impairment. Dysarthria and truncal hypotonia are observed. Cerebellar signs (truncal titubation and intention tremor) and peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals. Seizures can occur. In a few cases cataracts may be absent.

Diagnosis/testing. HCC can be diagnosed with confidence in individuals with typical clinical findings, characteristic abnormalities on brain MRI, and identifiable mutations in FAM126A (also known as DRCTNNB1A or HCC).

Management. Treatment of manifestations: Physical therapy to improve motor function; special education; antiepileptic drugs as needed.

Surveillance: Periodic neurologic evaluations to identify neurologic complications; evaluations by a physiatrist to aid with assistive devices as needed; eye examinations if cataracts are not identified in the neonatal period.

Genetic counseling. HCC 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. Individuals with HCC do not reproduce. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

Diagnosis

Clinical Diagnosis

Hypomyelination and congenital cataract (HCC) can be diagnosed with confidence in individuals with typical clinical findings [Biancheri et al 2007], characteristic abnormalities on brain MRI [Rossi et al 2008], and identifiable mutations in FAM126A (DRCTNNB1A) [Zara et al 2006].

Clinical findings

  • Bilateral congenital cataracts (One patient had juvenile cataract [Ugur & Tolun 2008]; one patient had only a mild lens opacity, which was noted at age 3 years [Biancheri et al 2011].)
  • Classical presentation: normal psychomotor development in the first year of life, followed by slowly progressive neurologic impairment manifest as:
    • Ataxia
    • Spasticity
    • Loss of the ability to walk
    • Mild to moderate cognitive impairment
  • Uncommon presentations [Biancheri et al 2011]:
    • Early-onset severe variant: hypotonia and feeding difficulties in the neonatal period, developmental delay in the first months of life, and wheelchair dependency in early childhood
    • Late-onset mild variant: normal development in the first two years of life with subsequent sudden motor regression

MRI findings

  • Diffusely abnormal supratentorial white matter in all individuals
  • Abnormal white matter signal behavior consistent with hypomyelination:
    • Hyperintense on T2-weighted images (intermediate hyperintensity between that of myelinated white matter and CSF) (Figure 1)
    • Isointense to slightly hypointense on T1-weighted images (Figure 2)
  • Areas of higher T2-weighted signal intensity with corresponding low-signal intensity on T1-weighted images consistent with areas of increased white matter water content of variable extension in some individuals (Figure 3)
  • White matter bulk loss and gliosis in older individuals (Figure 4)
  • Medullary centers of the cerebellar hemispheres showing mildly increased T2-weighted signal intensity, paralleling that of the adjacent cortical gray matter and resulting in a “blurred” gray-white matter interface in some individuals (Figure 5)
  • Sparing of the cortical and deep gray matter structures
Figure 1

Figure

Figure 1. Axial T2-weighted image shows diffuse hyperintensity of supratentorial white matter consistent with hypomyelination.

Figure 2

Figure

Figure 2. Axial T1-weighted image shows diffusely isointense white matter with poor demarcation from adjacent gray matter, consistent with hypomyelination.

Figure 3

Figure

Figure 3. Axial T1-weighted image (panel A) and axial T2-weighted image (panel B) show areas of increased water content involving the deep frontal white matter.

Figure 4

Figure

Figure 4. Axial T2-weighted image in a 15-year-old shows enlargement of ventricles and subarachnoid spaces consistent with cerebral atrophy. The periventricular white matter is more hyperintense than the subcortical white matter, suggesting superimposed (more...)

Figure 5

Figure

Figure 5. Coronal T2-weighted image shows poor gray-white matter demarcation at the level of the medullary centers of the cerebellum, suggesting abnormal myelination of the cerebellar white matter.

Testing

Routine laboratory tests are normal.

Molecular Genetic Testing

Gene. FAM126A (previously known as DRCTNNB1A or HCC) encodes the protein hyccin and is the only gene in which mutation is known to cause HCC.

Clinical testing

Research testing

  • Deletion/duplication analysis to detect exonic, multiexonic, and whole-gene deletions. One such analysis involving FAM126A identified a deletion in a proband from a large consanguineous Turkish family [Ugur & Tolun 2008]. Deletions were not detected in five additional families of Turkish and Italian ancestry [Zara et al 2006].

Table 1. Summary of Molecular Genetic Testing Used in Hypomyelination and Congenital Cataract

Gene Symbol 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
FAM126ASequence analysisSequence variants 45/6 probands analyzed
Deletion/ duplication analysis 5(Multi)exonic and whole-gene deletions1/6 probands analyzed

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies deletions/duplications not readily 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.

Testing Strategy

Confirming the diagnosis in a proband. Evaluate for the following:

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Hypomyelination and congenital cataract (HCC) phenotype is quite consistent in the ten affected individuals from five unrelated families described to date.

All affected individuals have normal prenatal and perinatal histories.

Bilateral congenital cataracts identified at birth or within the first month of life are the first clinical sign. All children underwent ocular surgery in the first months of life with the exception of the one child who had adolescent-onset cataracts [Ugur & Tolun 2008].

Psychomotor development is normal up until the end of the first year of life when developmental delays appear [Biancheri et al 2007]. The ability to walk with support is achieved between ages 12 and 24 months. Independent walking is not achieved in all individuals. Slowly progressive neurologic impairment then becomes apparent with gradual loss of the ability to walk. Most individuals become wheelchair bound between ages eight and nine years. A slowly progressive scoliosis appears concurrently with the loss of the ability to walk [Biancheri et al 2007].

Most individuals have mild to moderate intellectual disability without deterioration in cognitive ability over time.

Clinical examination reveals the following from the onset of the disease course:

  • Dysarthria
  • Truncal hypotonia
  • Brisk tendon reflexes and bilateral extensor plantar responses
  • Cerebellar signs, including truncal titubation and intention tremor, in most individuals
  • Peripheral neuropathy, present in most individuals, manifest as muscle weakness and wasting of the legs. Peripheral neuropathy is absent in individuals with a milder form of the disorder (see Genotype-Phenotype Correlations).

Seizures may occur, but are not a predominant clinical feature.

Life expectancy is unknown; the oldest living affected individual is age 29 years.

Neurophysiologic investigations show the following from the onset of the disease course:

  • Motor nerve conduction velocity. Slightly to markedly slowed in most individuals, with lower values in older persons
  • Compound muscle action potentials. Reduced amplitude
  • Electromyography. Signs of denervation in the absence of spontaneous activity
  • Waking EEG. Irregular background activity; multifocal epileptiform discharges may be recorded.
  • Brain stem auditory evoked potentials. Increased I-V interpeak conduction time in individuals older than age two years
  • Somatosensory evoked potentials. Increased central conduction time in all affected individuals
  • Flash visual evoked potentials. Normal
  • Electroretinogram. Normal

Neuropathologic findings

  • Sural nerve biopsy of individuals with peripheral neuropathy shows a slight-to-severe reduction in density of myelinated fibers, with several axons surrounded by a thin myelin sheath or devoid of myelin.
  • Uncompaction of the myelin sheath, which in some fibers appears redundant and irregularly folded, is occasionally seen.
  • Electron microscopy confirms the presence of axons devoid of myelin, together with thinly myelinated fibers, sometimes surrounded by few Schwann cells processes, forming small onion bulbs.

Genotype-Phenotype Correlations

Mutations leading to the complete absence of FAM126A protein expression are associated with the full phenotype of bilateral cataract, central nervous system hypomyelination, and peripheral nerve hypomyelination.

Mutations leading to a partial protein deficiency are associated with the milder form without peripheral nervous system involvement.

An individual with deletion of exons 8 and 9 did not have congenital cataracts; cataracts developed at age nine years. A second individual had congenital unilateral cataract. However, of the four children in this family who survived beyond age two years, none was able to walk with support after age six years [Ugur & Tolun 2008].

Because of the limited number of individuals with HCC described so far, these correlations should be further confirmed.

Penetrance

Penetrance is complete.

Prevalence

HCC is likely a rare disorder. No epidemiologic studies are available.

Differential Diagnosis

The association of congenital cataract and cerebral hypomyelination is typical of hypomyelination and congenital cataract (HCC). However, the differential diagnosis with other hypomyelinating disorders should include the following:

  • PLP1-related disorders of central nervous system myelin formation include a range of phenotypes from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD, the prototype hypomyelinating disorder, typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. Life span is shortened. SPG2 manifests as spastic paraparesis with or without central nervous system involvement and usually normal life span. Female carriers may manifest mild to moderate signs of the disease. Intrafamilial variation of phenotypes can be observed, but the signs are usually fairly consistent within families. Duplications, deletions, and point mutations in PLP1 are causative. Inheritance is X-linked.
  • The syndrome of early-onset nystagmus, delayed motor milestones, ataxia, progressive spasticity, partial seizures, mild peripheral neuropathy, and diffuse hypomeylination on MRI is caused by mutations in GJA12 (GJC2), encoding connexin 46.6 [Uhlenberg et al 2004]. Inheritance is autosomal recessive.
  • The allelic disorders of free sialic acid metabolism (see Free Sialic Acid Storage Disorders), Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD) are neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. The mildest phenotype is Salla disease, characterized by normal appearance and neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild to moderate psychomotor retardation, spasticity, athetosis, and epileptic seizures. In Salla disease, abnormal myelination of the basal ganglia and hypoplasia of the corpus callosum are constant and early findings [Sonninen et al 1999]. Cerebellar white matter changes are also present, and can explain the ataxia [Linnankivi et al 2003, Biancheri et al 2004]. The most severe phenotype of the free sialic acid storage disorders is ISSD. Affected individuals have severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly. Death usually occurs in early childhood. Mutations in SLC17A5 are causative. Inheritance is autosomal recessive.
  • Cockayne syndrome (CS) spans a spectrum that includes: CS type I, the "classic" form; CS type II, a more severe form with symptoms present at birth (also known as cerebro-oculo-facial syndrome [COFS] or Pena-Shokeir syndrome type II); CS type III, a milder form; and xeroderma pigmentosum-Cockayne syndrome (XP-CS).
    CS type I is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability; death typically occurs in the first or second decade.
    CS type II, or "connatal" CS, is characterized by growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye may be present. Affected children have early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Death usually occurs by age seven years.
    In both CS type I and type II, a characteristic "tigroid" pattern of demyelination in the subcortical white matter of the brain, multifocal calcium deposition, and relative preservation of neurons are observed [Itoh et al 1999]. Mutations in ERCC6 and ERCC8 are causative. Inheritance is autosomal recessive.
  • Trichothiodystrophy, or Tay syndrome, is characterized by growth retardation, intellectual disability, microcephaly, congenital ichthyosis, and brittle hair [van der Knaap & Valk 2005]. A DNA repair defect is causative. Inheritance is autosomal recessive.
  • Two other autosomal recessive hypomyelinating disorders show different clinical and imaging findings [van der Knaap et al 2002, Timmons et al 2006]:
    • Hypomyelination with atrophy of the basal ganglia and cerebellum syndrome (H-ABC)
    • Hypomyelination with hypogonadotropic hypogonadism and hypodontia syndrome

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software program that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with hypomyelination and congenital cataract (HCC), the following evaluations are recommended:

  • Ophthalmologic examination
  • Neurologic examination
  • Developmental assessment

Treatment of Manifestations

Cataract extraction, usually in the first months of life, is indicated.

Supportive therapy includes the following:

  • Physical therapy to improve motor function
  • Special education
  • Antiepileptic drugs if epileptic seizures are present

Surveillance

Periodic:

  • Neurologic evaluation to identify neurologic complications
  • Evaluation by a physiatrist to aid with assistive devices as needed
  • Eye examination if cataracts were not identified in the neonatal period

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 Clinical Trials.gov 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

Hypomyelination and congenital cataract (HCC) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

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.
  • 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.

Offspring of a proband. Individuals with HCC do not reproduce.

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

Carrier Detection

Carrier testing for at-risk family members is possible once the disease-causing mutations in the family have been identified.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations in the family have been identified, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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.

  • National Association for Parents of Children with Visual Impairments (NAPVI)
    PO Box 317
    Watertown MA 02471
    Phone: 800-562-6265 (toll-free); 617-972-7441
    Fax: 617-972-7444
    Email: napvi@perkins.org
  • National Dissemination Center for Children with Disabilities (NICHCY)
    1825 Connecticut Avenue NW
    Suite 700
    Washington DC 20009
    Phone: 800-695-0285 (Toll-free Voice/TTY); 202-884-8200 (Voice/TTY)
    Fax: 202-884-8441
    Email: nichcy@aed.org
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • Prevent Blindness America
    211 West Wacker Drive
    Suite 1700
    Chicago IL 60606
    Phone: 800-331-2020 (toll-free)
    Email: info@preventblindness.org
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.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. Hypomyelination and Congenital Cataract: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FAM126A7p15​.3HyccinFAM126A homepage - Mendelian genesFAM126A

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Hypomyelination and Congenital Cataract (View All in OMIM)

610531FAMILY WITH SEQUENCE SIMILARITY 126, MEMBER A; FAM126A
610532LEUKODYSTROPHY, HYPOMYELINATING, 5; HLD5

Normal allelic variants. FAM126A comprises 12 exons. Exon 11 is alternatively spliced. The most abundant isoform does not include exon 11 and is composed of 521 amino acids. The isoform including exon 11 is 399 amino acids long as s result of a premature stop codon on exon 11.

Pathologic allelic variants. See Table 2.

Table 2. Selected FAM126A Allelic Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
ReferenceReference Sequences
Normalc.624A>Gp.(=) 2
(Ser208Ser)
--rs3735231
Pathologicc.51+1G>A
(IVS2+1G>A)
--Zara et al [2006]NM_032581​.3
NP_115970​.2
c.414+1G>T
(IVS5+1G>T)
--Zara et al [2006]
c.158T>Cp.Leu53Pro Zara et al [2006]
(531-439_743+348del) (Arg209fs*213)Ugur & Tolun [2008]

Note on variant classification: Variants listed in the table have been provided by the author(s). 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. p.(=) indicates that the protein has not been analyzed, but no change is expected.

Normal gene product. FAM126A encodes a 521-amino acid membrane protein [Zara et al 2006] with unknown function. The protein contains two putative transmembrane domains but no known functional domains.

Abnormal gene product. Splicing mutations (c.414+1G>T and c.51+1G>A) lead to the premature truncation of protein by altering the mRNA splicing and lack of the protein. Missense mutation c.158T>C does not alter mRNA expression but leads to severe protein deficit through unknown cellular pathways. Genomic deletion is expected to cause a 308-amino acid deletion in the protein. The effect of the latter mutation was not investigated by immunoblot analysis.

References

Literature Cited

  1. Biancheri R, Rossi A, Mancini MG, Minetti C. Cerebellar white matter involvement in Salla disease. Neuroradiology. 2004;46:587–8. [PubMed: 15179531]
  2. Biancheri R, Zara F, Bruno C, Rossi A, Bordo L, Gazzerro E, Sotgia F, Pedemonte M, Scapolan S, Bado M, Uziel G, Bugiani M, Lamba LD, Costa V, Schenone A, Rozemuller AJ, Tortori-Donati P, Lisanti MP, van der Knaap MS, Minetti C. Phenotypic characterization of hypomyelination and congenital cataract. Ann Neurol. 2007;62:121–7. [PubMed: 17683097]
  3. Biancheri R, Zara F, Rossi A, Mathot M, Nassogne MC, Yalcinkaya C, Erturk O, Tuysuz B, Di Rocco M, Gazzerro E, Bugiani M, van Spaendonk R, Sistermans EA, Minetti C, van der Knaap MS, Wolf NI. Hypomyelination and congenital cataract: broadening the clinical phenotype. Arch Neurol. 2011;68:1191–4. [PubMed: 21911699]
  4. Itoh M, Hayashi M, Shioda K, Minagawa M, Isa F, Tamagawa K, Morimatsu Y, Oda M. Neurodegeneration in hereditary nucleotide repair disorders. Brain Dev. 1999;21:326–33. [PubMed: 10413020]
  5. Linnankivi T, Lönnqvist T, Autti T. A case of Salla disease with involvement of the cerebellar white matter. Neuroradiology. 2003;45:107–9. [PubMed: 12592494]
  6. Rossi A, Biancheri R, Zara F, Bruno C, Uziel G, van der Knaap MS, Minetti C, Tortori-Donati P. Hypomyelination and congenital cataract: neuroimaging features of a novel inherited white matter disorder. AJNR Am J Neuroradiol. 2008;29:301–5. [PubMed: 17974614]
  7. Sonninen P, Autti T, Varho T, Hämäläinen M, Raininko R. Brain involvement in Salla disease. AJNR Am J Neuroradiol. 1999;20:433–43. [PubMed: 10219409]
  8. Timmons M, Tsokos M, Asab MA, Seminara SB, Zirzow GC, Kaneski CR, Heiss JD, van der Knaap MS, Vanier MT, Schiffmann R, Wong K. Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia. Neurology. 2006;67:2066–9. [PMC free article: PMC1950601] [PubMed: 17159124]
  9. Ugur SA, Tolun A. A deletion in DRCTNNB1A associated with hypomyelination and juvenile onset cataract. Eur J Hum Genet. 2008;16:261–4. [PubMed: 17928815]
  10. Uhlenberg B, Schuelke M, Rüschendorf F, Ruf N, Kaindl AM, Henneke M, Thiele H, Stoltenburg-Didinger G, Aksu F, Topaloğlu H, Nürnberg P, Hübner C, Weschke B, Gärtner J. Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am J Hum Genet. 2004;75:251–60. [PMC free article: PMC1216059] [PubMed: 15192806]
  11. van der Knaap MS, Naidu S, Pouwels PJ, Bonavita S, van Coster R, Lagae L, Sperner J, Surtees R, Schiffmann R, Valk J. New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum. AJNR Am J Neuroradiol. 2002;23:1466–74. [PubMed: 12372733]
  12. van der Knaap MS, Valk J. Magnetic Resonance of Myelination and Myelin Disorders. 3 ed. Berlin, Germany: Springer; 2005.
  13. Zara F, Biancheri R, Bruno C, Bordo L, Assereto S, Gazzerro E, Sotgia F, Wang XB, Gianotti S, Stringara S, Pedemonte M, Uziel G, Rossi A, Schenone A, Tortori-Donati P, van der Knaap MS, Lisanti MP, Minetti C. Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract. Nat Genet. 2006;38:1111–3. [PubMed: 16951682]

Chapter Notes

Acknowledgments

We thank the Cell Line and DNA Bank from Patients Affected by Genetic Diseases collection (dppm.gaslini.org/biobank), supported by the Italian Telethon, for allowing us to obtain samples.

Revision History

  • 27 October 2011 (cd) Revision: mutation scanning and deletion/duplication analysis no longer available clinically; sequence analysis now available clinically
  • 27 January 2011 (cd) Revision: prenatal testing available clinically
  • 16 November 2010 (me) Comprehensive update posted live
  • 14 October 2008 (me) Review posted live
  • 14 May 2008 (rb) Original submission
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