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

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

Figure

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

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

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

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

• Sequence analysis of FAM126A is available clinically. Missense and splice-site mutations in five of six probands were identified by sequence analysis of the entire coding region and the exon-intron boundaries of FAM126A [Zara et al 2006, Ugur & Tolun 2008].

Research testing

• Deletion/duplication analysis. Testing for the detection of exonic, multiexonic, and whole-gene deletions is available clinically. 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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
FAM126A	Sequence analysis	Sequence variants 2	5/6 probands analyzed	Clinical
	Deletion / duplication analysis 3	Exonic, multiexonic, and whole-gene deletions	1/6 probands analyzed	Research only

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

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

• Typical clinical findings

• Characteristic abnormalities on brain MRI

• Identifiable FAM126A mutations, first by mutation scanning followed by deletion/duplication analysis if only one or no mutations are identified by scanning.

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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in FAM126A.

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.

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.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

Myelin Disorders Bioregistry Project
Phone: 202-476-6230
Email: myelin@cnmc.org
Web: www.myelindisorders.org

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must have been identified before prenatal testing can be performed.

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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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: 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]

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