Clinical Diagnosis

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder, is characterized by [Dupré et al 2003]:

• Severe progressive sensorimotor neuropathy with resulting hypotonia, areflexia, and amyotrophy

• Variable degree of dysgenesis of the corpus callosum (Figures 1A and 2A; Figures 1B and 2B show comparable MRIs of normal brains). Magnetic resonance imaging shows complete callosal agenesis in 60% of individuals, partial callosal agenesis in 10%, and normal corpus callosum in 30%. Mild cortical or cerebellar atrophy may be observed in older persons.

Figure

Figure 1. Sagittal T1-weighted MRI
A. Complete agenesis of the corpus callosum
B. Normal corpus callosum

Figure

Figure 2. Axial T1-weighted MRI
A. Agenesis of the corpus callosum with parallelism of the ventricles
B. Normal ventricles

Electrophysiology. Sensorimotor neuropathy can be confirmed on electrophysiologic testing:

• Sensory nerve action potentials cannot be recorded at the median, ulnar, or sural nerves even in children in their first year of life.

• Compound motor action potentials (CMAP) usually show diminished amplitudes.

• Nerve conduction velocities (NCVs) for the median, ulnar, and tibial nerves are variable.

• Needle electromyography (EMG) may show mild signs of active denervation such as fibrillation potentials.

Molecular Genetic Testing

Gene. SLC12A6 is the only gene currently known to be associated with HMSN/ACC [Howard et al 2002].

Clinical testing

• Targeted mutation analysis

  • The exon 18 mutation (c.2436delG) is the one found in almost all (>99%) individuals of French-Canadian descent.

  • The exon 11 mutation (c.1584_1585delCTinsG) was found in a single individual of French-Canadian origin who is a compound heterozygote [Howard et al 2002].

• Sequence analysis. Sequencing of all exons has an estimated detection rate of over 90%.

• Sequence analysis/mutation scanning. Individuals who are not of French-Canadian origin can be evaluated for the following mutations:

  • c.2023C>T if they are from northern Italy

  • c.901delA or c.619C>T if they are from Turkey

  • c.2031_2032insT or c.1478_1485delTTCCCTCT if they are from Germany

  • del+2994-3003 if they are of Sudanese origin

Note: c.3031C>T can be considered a hot-spot since it can occur on different haplotypes (Dutch-Afrikaner and Turkish) [Dupré et al 2003, Salin-Cantegrel et al 2007, Uyanik et al 2006].

Table 1. Summary of Molecular Genetic Testing Used in Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum (HMSN/ACC)

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
SLC12A6	Targeted mutation analysis	c.2436delG	100% 1	Clinical
	Sequence analysis of coding region	Sequence variants	~90%

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. Individuals of French-Canadian origin

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

Testing Strategy

To establish the diagnosis in a proband

• Probands should initially undergo:

  • Neurologic examination

  • Brain magnetic resonance imaging to evaluate the corpus callosum

  • Electrophysiologic studies to confirm the presence of a sensorimotor neuropathy

• For probands of French-Canadian origin who have the typical phenotype, the exon 18 mutation should be tested initially, followed by sequence analysis.

• For probands of other ethnic origins, sequence analysis of the entire coding region should be performed.

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.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in the SLC12A6 gene.

Natural History

The main features of HMSN/ACC in the French-Canadian population were reported by Larbrisseau et al [1984] and Mathieu et al [1990].

In a study of 64 individuals between ages two and 34 years, the following neurologic findings were observed:

• Reflexes invariably absent from infancy

• Hypotonia invariably present in the first year of life

• Progressive distal and proximal symmetric limb weakness

• Muscle atrophy

• Diffuse limb tremor (probably resulting from the polyneuropathy)

• Moderate to severe abnormalities of all sensory modalities from infancy

The following cranial nerve involvement was observed:

• Eyelid ptosis (59%), symmetric or asymmetric

• Facial weakness (34%), symmetric or asymmetric that may be associated with hemi-facial atrophy

• Esotropia or exotropia, resulting from variable combinations of oculomotor nerve palsies

• Gaze palsy (30%)

• Horizontal nystagmus

Cognitive function of individuals with HMSN/ACC has been addressed in relatively few studies. Using the clinical classification of Taft to stratify cognitive function in 53 individuals, Mathieu et al [1990] found that 8% had normal intelligence, 49% had mild mental retardation, 40% had moderate mental retardation, and 4% had severe mental retardation.

Mathieu et al [1990] reported that after age 15 years, 39% (25/64) developed "psychotic episodes" characterized by paranoid delusions, depressive states, visual hallucinations, auditory hallucinations, or "autistic-like" features.

Other findings:

• Scoliosis (86%)

• Early Achilles' tendon retraction (47%)

• Seizures (17%)

• Pulmonary restrictive syndrome

Dysmorphic features may include ocular hypertelorism (usually mild); brachycephaly (16%); high-arched palate (39%); overriding of the first toe (16%); and partial syndactyly of 2nd-3rd toes (8%).

The average age of onset of walking is 3.8 years, average age of loss of ability to walk is 13.8 years, average age of appearance of scoliosis is 10.4 years, and average age of death is 33 years.

Other

• Lumbar puncture usually reveals mild elevation of CSF proteins.

• Sural nerve biopsy shows an almost total lack of large myelinated fibers, signs of axonal loss (ovoids of Wallerian degeneration), and some enlarged axons that on electron microscopy show decreased density of neurofilaments. Isolated fibers may have disproportionately thin myelin sheaths, suggesting that the axoplasm is swollen. Electron microscopy may show decreased packing density of neurofilaments, without signs of their degradation.
  
  Note: Sural nerve biopsy is unnecessary to confirm the diagnosis, now that molecular genetic testing is available.

• Muscle biopsy shows nonspecific signs of chronic denervation atrophy.

• Autopsy examination. The hallmark is swollen axons in cranial nerve samples (especially cranial nerves 3 and 7), as well as in the dorsal and ventral nerve roots. Swollen axons can also be scattered in the white matter. The brain shows either absence of the ACC, partial ACC, or complete ACC with preservation of Probst bundle.

Genotype-Phenotype Correlations

In the French-Canadian population, the exon 18 mutation is present in almost all affected individuals. A single individual was identified as a compound heterozygote for the exon 18 mutation and the exon 11 mutation, and this individual's phenotype did not differ significantly from that of the other individuals of French-Canadian descent.

Mutations in SLC12A6 have been confirmed in only two non-French-Canadian families whose phenotype was similar to that in individuals of French-Canadian origin [Dupré et al 2003]:

• A brother (age four years) and his sister (age five years) from the region of Verona, Italy, born to unrelated unaffected parents, had developmental delay, a sensory-motor axonal polyneuropathy, and callosal agenesis. Both have the SLC12A6 mutation c.2023C>T, in exon 15.

• Two boys of Turkish origin, born to unaffected parents who are second-degree cousins, had developmental delay, areflexia, hypotonia, a sensory-motor polyneuropathy, and complete callosal agenesis. Both have the SLC12A6 nonsense mutation c.3031C>T, in exon 22.

Prevalence

In the French-Canadian population of the Saguenay and Lac-St-Jean regions of Quebec, Canada, the overall incidence of HMSN/ACC is 1:2117 live births; the carrier rate is 1:23 inhabitants.

Otherwise, HMSN/ACC is extremely rare worldwide. Only two pairs of siblings (of Italian and Turkish origin) have been reported to have molecularly-confirmed HMSN/ACC.

A Tanzanian family has been described (without genetic testing) in which one of three affected siblings had only ACC [Deleu et al 1997].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with hereditary motor and sensory neuropathy with agenesis of the corpus callosum, the following evaluations are recommended:

• Developmental assessment

• Physical therapy assessment to determine strength and self-help skills

Treatment of Manifestations

During the first few years of life, most children with HMSN/ACC are able to achieve walking independently, but require walking aids such as canes or walkers.

Early developmental/educational intervention is appropriate for cognitive delays.

Depending on its degree of severity, scoliosis usually requires surgical correction.

Low-dose neuroleptics may be useful for psychiatric manifestations. Referral for psychiatric evaluation is appropriate.

Prevention of Primary Manifestations

No specific treatment is available for the sensorimotor neuropathy.

Care is best provided by a multidisciplinary team that comprises a pediatrician or pediatric neurologist, an orthopedist, a physiotherapist, and an occupational therapist.

Prevention of Secondary Complications

As the disease progresses in childhood various orthoses for the upper and lower limbs are needed.

Regular physiotherapy is required to prevent contractures of the hands and feet.

Surveillance

The following are appropriate:

• Orthopedic follow-up, especially during the early teens when significant scoliosis starts to appear

• Monitoring in the late teens for psychiatric manifestations including psychosis and paranoid delusions

Testing 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. Note: There may not be clinical trials for this disorder.

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

HMSN/ACC 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 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 HMSN/ACC 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 mutations have been identified 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 carriers or at risk of being carriers.

DNA banking. 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. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. 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. Both disease-causing alleles of an affected family member must be 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 .

Literature Cited

1. Boettger T, Rust MB, Maier H, Seidenbecher T, Schweizer M, Keating DJ, Faulhaber J, Ehmke H, Pfeffer C, Scheel O, Lemcke B, Horst J, Leuwer R, Pape HC, Völkl H, Hübner CA, Jentsch TJ. Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO J. 2003;22:5422–34. [PMC free article: PMC213773] [PubMed: 14532115]
2. Deleu D, Bamanikar SA, Muirhead D, Louon A. Familial progressive sensorimotor neuropathy with agenesis of the corpus callosum (Andermann syndrome): a clinical, neuroradiological and histopathological study. Eur Neurol. 1997;37:104–9. [PubMed: 9058066]
3. Dupré N, Howard HC, Mathieu J, Karpati G, Vanasse M, Bouchard JP, Carpenter S, Rouleau GA. Hereditary motor and sensory neuropathy with agenesis of the corpus callosum. Ann Neurol. 2003;54:9–18. [PubMed: 12838516]
4. Howard HC, Mount DB, Rochefort D, Byun N, Dupré N, Lu J, Fan X, Song L, Rivière JB, Prévost C, Horst J, Simonati A, Lemcke B, Welch R, England R, Zhan FQ, Mercado A, Siesser WB, George AL, McDonald MP, Bouchard JP, Mathieu J, Delpire E, Rouleau GA. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet. 2002;32:384–92. [PubMed: 12368912]
5. Larbrisseau A, Vanasse M, Brochu P, Jasmin G. The Andermann syndrome: agenesis of the corpus callosum associated with mental retardation and progressive sensorimotor neuronopathy. Can J Neurol Sci. 1984;11:257–61. [PubMed: 6329500]
6. Mathieu J, Bédard F, Prévost C, Langevin P. Can J Neurol Sci. 1990;17:103–8. [PubMed: 2357646]
7. Mercado A, Vázquez N, Song L, Cortés R, Enck AH, Welch R, Delpire E, Gamba G, Mount DB. NH2-terminal heterogeneity in the KCC3 K+-Cl- cotransporter. Am J Physiol Renal Physiol. 2005;289:F1246–61. [PubMed: 16048901]
8. Salin-Cantegrel A, Rivière JB, Dupré N, Charron FM, Shekarabi M, Karéméra L, Gaspar C, Horst J, Tekin M, Deda G, Krause A, Lippert MM, Willemsen MA, Jarrar R, Lapointe JY, Rouleau GA. Distal truncation of KCC3 in non-French Canadian HMSN/ACC families. Neurology. 2007;69:1350–5. [PubMed: 17893295]
9. Uyanik G, Elcioglu N, Penzien J, Gross C, Yilmaz Y, Olmez A, Demir E, Wahl D, Scheglmann K, Winner B, Bogdahn U, Topaloglu H, Hehr U, Winkler J. Neurology. 2006;66:1044–8. [PubMed: 16606917]

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Reading

1. Dupré N, Mathieu J, Chicoine L, Leveille D (2004) La neuropathie sensitivomotrice hereditaire avec ou sans agenesie du corps calleux. In: Vanasse M, Pare H, Brousseau Y, D'Arcy S (eds) Les maladies neuromusculaires chez l'enfant et l'adolescent. Editions de l'Hopital Ste-Justine (CHU mere-enfant), Montreal. 2004:209-18.

Acknowledgments

This work was supported by La Fondation des Jumelles Coudé and the Canadian Institute of Health Research.

Additionally, the authors would like to acknowledge the very significant contribution of Dr. Jean Mathieu and Dr. Jean-Pierre Bouchard to the understanding of HMSN/ACC, which has been the cornerstone of its phenotypic and genotypic characterization in the last decade.

Revision History

• 18 June 2009 (me) Comprehensive update posted live

• 2 February 2006 (me) Review posted to live Web site

• 2 September 2005 (gr) Original submission