Clinical characteristics.

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder, is characterized by severe progressive sensorimotor neuropathy with resulting hypotonia, areflexia, and amyotrophy, and by variable degrees of dysgenesis of the corpus callosum. Mild-to-severe intellectual disability and "psychotic episodes" during adolescence are observed. Sensory modalities are moderately to severely affected beginning in infancy. The average age of onset of walking is 3.8 years; the average age of loss of walking is 13.8 years; the average age of death is 33 years.

Diagnosis/testing.

The diagnosis of HMSN/ACC is established in a proband with suggestive findings and biallelic pathogenic variants in SLC12A6 identified by molecular genetic testing.

Management.

Treatment of manifestations: Walking aids such as canes or walkers are required. As the disease progresses, orthoses for upper and lower limbs and physiotherapy are needed to prevent contractures. Early developmental/educational intervention addresses cognitive delays. Depending on severity, individuals with HMSN/ACC usually require corrective surgery for scoliosis. Neuroleptics may be used to treat psychiatric manifestations, usually during adolescence.

Surveillance: Monitor in the early teens for scoliosis and in the late teens for psychiatric manifestations.

Genetic counseling.

HMSN/ACC 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. Heterozygotes (carriers) are asymptomatic. Once the SLC12A6 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) should be suspected in individuals with the following clinical, electrophysiologic, and neuroimaging findings, and family history [Dupré et al 2003].

Clinical findings

• Severe progressive sensorimotor neuropathy with areflexia
• Developmental delay / intellectual disability ranging from mild to severe

Electrophysiology

• 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 usually show diminished amplitudes.
• Nerve conduction velocities for the median, ulnar, and tibial nerves are variable.
• Needle electromyography may show mild signs of active denervation (e.g., fibrillation potentials).

Neuroimaging

• Brain MRI showing complete agenesis of the corpus callosum in 60% of individuals (Figure 1A, 2A), partial agenesis in 10%, and normal corpus callosum in 30% (Figure 1B, 2B)
• Mild cortical or cerebellar atrophy at a later age

Figure 1.

Sagittal T₁-weighted MRI A. Complete agenesis of the corpus callosum

Figure 2.

Axial T₁-weighted MRI A. Agenesis of the corpus callosum with parallelism of the ventricles

Family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is established in a proband with suggestive findings and biallelic pathogenic variants in SLC12A6 identified by molecular genetic testing (see Table 1).

Note: Identification of biallelic SLC12A6 variants of uncertain significance (or identification of one known SLC12A6 pathogenic variant and one SLC12A6 variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.

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

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of HMSN/ACC has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is both a neurodevelopmental disorder (with variable degrees of dysgenesis of the corpus callosum and mild-to-severe intellectual disability) and a neurodegenerative disorder (severe progressive sensorimotor neuropathy).

The neurologic findings of HMSN/ACC in 64 individuals (ages 2 to 34 years) in the French Canadian population reported by Mathieu et al [1990] are summarized in Table 2, with additional information from Larbrisseau et al [1984], Salin-Cantegrel et al [2007], and Auer et al [2016].

Progressive motor and sensory neuropathy

• 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 secondary to polyneuropathy)
• Contractures
• Loss of sensation to touch and pinprick in a glove and stocking distribution; easier to evaluate in older children

The average age of onset for sitting alone is 2.1 years, for standing is more than two years, for walking is 3.8 years, and average age of loss of ability to walk is 13.8 years.

Cognitive function. The Taft clinical classification uses an IQ test to rank individuals in four categories: normal intelligence (IQ >75), mild intellectual disability (IQ = 50-75), moderate intellectual disability (IQ = 25-50), and severe intellectual disability (IQ <25). Individuals with mild intellectual disability can achieve five to six years of elementary school and live independently. Individuals with moderate intellectual disability can help with activities of daily living but require supervision on a daily basis. Individuals with severe intellectual disability require assistance for daily living and supervision but may be able to take care of some routine daily needs. The range of intelligence of individuals with HSMN/ACC is normal IQ to severe intellectual disability.

Psychotic episodes. 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.

Life expectancy. Average age of death is 33 years and is usually related to respiratory insufficiency [Larbrisseau & Sarnat 2017].

Other

• Lumbar puncture usually reveals mild elevation of CSF proteins [Dupré et al 2003].
• 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 [Dupré et al 2003, Auer et al 2016].
  Note: Sural nerve biopsy is unnecessary to confirm the diagnosis, now that molecular genetic testing is possible.
• EEG may be normal or with epileptiform abnormalities [Dupré et al 2003, Salin-Cantegrel et al 2007].
• Muscle biopsy shows nonspecific signs of chronic denervation atrophy [Dupré et al 2003, Auer et al 2016].

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 no agenesis of the corpus callosum (ACC), partial ACC, or complete ACC with preservation of Probst bundle [Dupré et al 2003, Auer et al 2016].

Genotype-Phenotype Correlations

The data from affected individuals are insufficient to establish genotype-phenotype correlations.

Nomenclature

HMSN/ACC may also be referred to as Charlevoix disease.

Prevalence

In the French Canadian population of the Saguenay and Lac-St-Jean regions of Quebec, Canada, the overall incidence of HMSN/ACC is 1:2,117 live births; the carrier rate is 1:23 inhabitants due to the c.2436+1delG (also known as c.2436delG) founder variant. Otherwise, HMSN/ACC is extremely rare worldwide. Three pairs of sibs (of Italian, Mexican, and Turkish origin) have been reported to have molecularly confirmed HMSN/ACC.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

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