CORPUS CALLOSUM, AGENESIS OF, WITH NEURONOPATHY
POLYNEUROPATHY, SENSORIMOTOR, WITH OR WITHOUT AGENESIS OF THE CORPUS CALLOSUM
ACCPN
charlevoix disease
andermann syndrome
Genetic syndrome with corpus callosum agenesis /dysgenesis as a major feature
-Rare genetic disease
Spinal muscular atrophy associated with central nervous system anomaly
-Rare genetic disease
-Rare neurologic disease
Syndrome with corpus callosum agenesis /dysgenesis as a major feature
-Rare developmental defect during embryogenesis
-Rare neurologic disease
Andermann syndrome is an autosomal recessive motor and sensory neuropathy with agenesis of the corpus callosum associated with developmental and neurodegenerative defects and dysmorphic features. It has a high prevalence in the French Canadian population in the Charlevoix ... Andermann syndrome is an autosomal recessive motor and sensory neuropathy with agenesis of the corpus callosum associated with developmental and neurodegenerative defects and dysmorphic features. It has a high prevalence in the French Canadian population in the Charlevoix and Saguenay-Lac-Saint-Jean region of Quebec (Uyanik et al., 2006). Dupre et al. (2003) provided a comprehensive review of the disorder. Dobyns (1996) reviewed the many genetic causes of agenesis of the corpus callosum.
Naiman and Fraser (1955) described 2 sisters, and Ziegler (1958) described 2 brothers with agenesis of the corpus callosum associated with mental and physical retardation. Andermann et al. (1972) observed 2 brothers with mental retardation, areflexia and paraparesis. ... Naiman and Fraser (1955) described 2 sisters, and Ziegler (1958) described 2 brothers with agenesis of the corpus callosum associated with mental and physical retardation. Andermann et al. (1972) observed 2 brothers with mental retardation, areflexia and paraparesis. The authors postulated an anterior horn cell disease. The clinical picture was the same as in the sisters reported by Naiman and Fraser (1955) and the 2 families were French Canadian from the Charlevoix County in Quebec. Andermann et al. (1977) extended these studies to identify 45 patients in 24 sibships, descendants from a couple married in Quebec City, Charlevoix County, in 1657. Brain CT imaging demonstrated agenesis of the corpus callosum. Cao et al. (1977) reported 3 sibs, a male and 2 females, with severe mental retardation, spastic quadriplegia, microcephaly, and infantile spasms. Two sibs had agenesis of the corpus callosum on pneumoencephalogram. Other reports of familial agenesis of the corpus callosum consistent with autosomal recessive inheritance were published by Shapira and Cohen (1973) and Castro Gago et al. (1982). The former report concerned 2 affected sisters whose parents were more closely related than first cousins. The latter report concerned 2 sisters and 2 daughters of a paternal uncle of their father. The 2 sisters, studied at 6 years and 15 months of age, respectively, had progressive psychomotor regression, microcephaly, optic atrophy and seizures. CT scan showed absence of the corpus callosum, subcortical atrophy and gray substance heterotopy at the level of the ventricles. Larbrisseau et al. (1984) studied 15 cases and described a characteristic dysmorphic facies. The authors observed that progressive motor neuropathy led to loss of ambulation by adolescence and progressive scoliosis. Hauser et al. (1993) reported cases of agenesis of the corpus callosum with neuronopathy in a brother and sister in Vienna. Uyanik et al. (2006) reported 3 unrelated patients with Andermann syndrome; 1 was German and 2 Turkish. The German child presented at age 13 days with feeding difficulties and hypotonia. Over the next few months, she was found to have complete absence of the corpus callosum with ventricular enlargement and areflexia with an axonal and demyelinating peripheral neuropathy. Lumbar puncture showed increased CSF protein. At age 3 years, she had marked psychomotor retardation with inability to walk or speak. Mild facial dysmorphism was present, including hypertelorism, short nose, broad nasal root, and downplaced first toe and thumb. The second child, born of consanguineous Turkish parents, presented with diffuse hypotonic weakness, psychomotor retardation, and afebrile seizures. She had mild mental retardation, high-arched palate, elongated facies, esotropia of the right eye, ptosis, facial diplegia, areflexia, and distal wasting of the limbs. She had complete ACC and an axonal/demyelinating motor and sensory neuropathy with decreased nerve conduction velocities. The third child, born of second-degree Turkish cousins, had hypotonia and psychomotor retardation. He could walk with support at age 5 years and developed some speech. He had complete ACC and peripheral neuropathy but was less severely affected in the upper limbs. He also had bilateral diffuse white matter abnormalities, which had not previously been reported in this syndrome.
The K-Cl cotransporter KCC3, encoded by the SLC12A6 gene, maps within the ACCPN candidate region, prompting Howard et al. (2002) to screen that gene for mutations in individuals with ACCPN. Four distinct protein-truncated mutations (604878.0001-604878.0004) were found: 2 ... The K-Cl cotransporter KCC3, encoded by the SLC12A6 gene, maps within the ACCPN candidate region, prompting Howard et al. (2002) to screen that gene for mutations in individuals with ACCPN. Four distinct protein-truncated mutations (604878.0001-604878.0004) were found: 2 in the French Canadian population and 2 in non-French Canadian families. A 1-bp deletion (2436delG; 604878.0001) was determined to be a founder mutation in the French Canadian population. In 3 unrelated patients with Andermann syndrome, Uyanik et al. (2006) identified 4 different mutations in the SLC12A6 gene (604878.0005-704878.0008). Two were of Turkish descent, and 1 was German. Salin-Cantegrel et al. (2007) identified 2 mutations in exon 22 of the SLC12A6 gene (604878.0003; 604878.0009) in non-French Canadian patients with ACCPN, including families from Turkey, South Africa, Sudan, and the Netherlands.
De Braekeleer et al. (1993) estimated that in the Saguenay-Lac-Saint-Jean region of northeastern Quebec the incidence at birth was 1 in 2,117 liveborns, and the carrier rate was 1 in 23 inhabitants. Remote consanguinity was found in several ... De Braekeleer et al. (1993) estimated that in the Saguenay-Lac-Saint-Jean region of northeastern Quebec the incidence at birth was 1 in 2,117 liveborns, and the carrier rate was 1 in 23 inhabitants. Remote consanguinity was found in several families, while the mean kinship coefficient was 2.7 times higher in the polyneuropathic group than in control groups. Genealogic reconstruction suggested that the high incidence is probably the result of founder effect and that a unique mutation accounts for most, if not all, of the cases known in this region. Howard et al. (2002) determined that a 1-bp deletion (2436delG) was a founder mutation in the French Canadian population.
Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder, is characterized by the following [Dupré et al 2003]:...
DiagnosisClinical DiagnosisHereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder, is characterized by the following [Dupré et al 2003]:Severe progressive sensorimotor neuropathy with resulting hypotonia, areflexia, and amyotrophyVariable 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.FigureFigure 1. Sagittal T1-weighted MRI A. Complete agenesis of the corpus callosum B. Normal corpus callosum FigureFigure 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 TestingGene. SLC12A6 is the only gene currently known to be associated with HMSN/ACC [Howard et al 2002].Clinical testingTargeted mutation analysisThe 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 Italyc.901delA or c.619C>T if they are from Turkeyc.2031_2032insT or c.1478_1485delTTCCCTCT if they are from Germanydel+2994-3003 if they are of Sudanese originNote: 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)View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySLC12A6Targeted mutation analysisc.2436delG 100% 2Clinical Sequence analysis of coding regionSequence variants 3~90%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Individuals of French-Canadian origin3. 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. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo establish the diagnosis in a probandProbands should initially undergo:Neurologic examinationBrain magnetic resonance imaging to evaluate the corpus callosumElectrophysiologic studies to confirm the presence of a sensorimotor neuropathyFor 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) DisordersNo other phenotypes are known to be associated with mutations in SLC12A6.
The main features of HMSN/ACC in the French-Canadian population were reported by Larbrisseau et al [1984] and Mathieu et al [1990]....
Natural HistoryThe 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 infancyHypotonia invariably present in the first year of lifeProgressive distal and proximal symmetric limb weaknessMuscle atrophyDiffuse limb tremor (probably resulting from the polyneuropathy)Moderate to severe abnormalities of all sensory modalities from infancyThe following cranial nerve involvement was observed:Eyelid ptosis (59%), symmetric or asymmetricFacial weakness (34%), symmetric or asymmetric that may be associated with hemi-facial atrophyEsotropia or exotropia, resulting from variable combinations of oculomotor nerve palsiesGaze palsy (30%)Horizontal nystagmusCognitive 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 intellectual disability, 40% had moderate intellectual disability, and 4% had severe intellectual disability.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 syndromeDysmorphic 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.OtherLumbar 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 possible.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.
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. ...
Genotype-Phenotype CorrelationsIn 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.
Severe early-onset autosomal recessive hereditary neuropathies (i.e., those classified as Charcot-Marie-Tooth hereditary neuropathy type 4, CMT4) may be considered as a differential diagnosis....
Differential DiagnosisSevere early-onset autosomal recessive hereditary neuropathies (i.e., those classified as Charcot-Marie-Tooth hereditary neuropathy type 4, CMT4) may be considered as a differential diagnosis.Infantile neuroaxonal dystrophy (INAD), or Seitelberger disease, comprises a classic form and an atypical form. Classic disease usually begins between ages six months and three years with hypotonia, progressive psychomotor delay, and symmetric pyramidal tract signs. Strabismus, nystagmus, and optic atrophy are common. Disease progression is rapid. Many affected children never learn to walk or lose this ability shortly after attaining it. Severe spasticity, progressive cognitive decline, and visual impairment typically result in death during the first decade. The atypical form is more varied than the classic form. In general, onset is in early childhood, but can be as late as the late teens. The presenting signs may be similar to the classic form with gait instability or ataxia, but may be speech delay and autistic features, which may remain as the only evidence of disease for a year or more. The course is fairly stable during early childhood and resembles static encephalopathy, but is followed by neurologic deterioration between ages seven and 12 years. PLA2G6 is the only gene known to be associated with classic and atypical NAD. Sequence analysis detects mutations in about 85% of affected individuals. Inheritance is autosomal recessive. Arylsulfatase A deficiency (metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile MLD (50%-60% of cases); juvenile MLD (20%-30% of cases); and adult MLD (15%-20% of cases). Infantile- and early-juvenile-onset MLD are included in the differential diagnosis of HMSN/ACC because children present with CNS and/or peripheral nervous system symptoms. Age of onset within a family is usually similar. All individuals eventually lose motor and intellectual functions. The disease course may be from three to ten or more years in the late infantile-onset form and up to 20 years or more in the juvenile- and adult-onset forms. Death most commonly results from pneumonia or other infection. The diagnosis is suggested by arylsulfatase A enzyme activity in leukocytes that is less than 10% of normal controls and is confirmed using one or more of the following additional tests: molecular genetic testing of ARSA, urinary excretion of sulfatides, and/or finding of metachromatic lipid deposits in nervous system tissue. Inheritance is autosomal recessive.Giant axonal neuropathy (GAN) is characterized by a severe early-onset peripheral motor and sensory neuropathy, central nervous system involvement (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs), and characteristic tightly curled hair. Most individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade. The diagnosis of GAN is established by clinical findings including nerve conduction velocity (NCV), brain MRI, and peripheral nerve biopsy. The pathologic hallmark is so-called giant axons caused by the accumulation of neurofilaments. GAN is caused by mutations in GAN, encoding the protein gigaxonin. GAN is the only gene currently known to be associated with GAN; however, there is evidence for genetic heterogeneity. Inheritance is autosomal recessive.
To establish the extent of disease in an individual diagnosed with hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), the following evaluations are recommended:Developmental assessmentPhysical therapy assessment to determine strength and self-help skillsTreatment of ManifestationsDuring 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 ManifestationsNo 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 ComplicationsAs 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.SurveillanceThe following are appropriate:Orthopedic follow-up, especially during the early teens when significant scoliosis starts to appearMonitoring in the late teens for psychiatric manifestations including psychosis and paranoid delusionsEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSLC12A615q14Solute carrier family 12 member 6IPN Mutations, SLC12A6 SLC12A6 homepage - Leiden Muscular Dystrophy pagesSLC12A6Data 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 Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum (View All in OMIM) View in own window 218000AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY; ACCPN 604878SOLUTE CARRIER FAMILY 12 (SODIUM/CHLORIDE TRANSPORTER), MEMBER 6; SLC12A6Normal allelic variants. SLC12A6 has a total of 26 coding exons, as well as two 5' non-coding exons that are not present in all transcripts. The two major transcripts of SLC12A6 are referred to as KCC3a and KCC3b, which utilize different first coding exons. KCC3a is composed of exon 1a plus exons 2-25, while KCC3b has exon 1b plus exons 2-25. A minimum of four other transcripts differ at the N-terminus because of alternative first exons and/or alternative splicing [Mercado et al 2005].Pathologic allelic variants. See Table 2.Table 2. Selected SLC12A6 Pathologic Allelic VariantsView in own windowEthnicityDNA Nucleotide Change Protein Amino Acid ChangeReference Sequences French-Canadianc.2436delGp.Thr813Profs*2AF105366.1 AAD39742.1French-Canadianc.1584_1585delCTinsGp.Phe529Leufs*4Italianc.2023C>Tp.Arg675XTurkc.3031C>Tp.Arg1011XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). Normal gene product. The predicted KCC3 protein structure includes 12 putative membrane-spanning helices with large NH2 and COOH termini, a large extracellular loop between transmembrane domains seven and eight with five potential sites for N-linked glycosylation, two consensus cAMP-dependant protein kinase phosphorylation sites, and four consensus protein kinase C phosphorylation sites in the COOH terminus. KCC3 could be involved either in volume regulation, in transepithelial transport of salt and water, or in regulation of K and Cl concentrations in cells and in the interstitial space. KCC3 may be involved in ion homeostasis (Cl- equilibrium) with a possible role in cell proliferation via ion-sensitive kinases [Howard et al 2002].Abnormal gene product. The truncated mutant protein is appropriately glycosylated and expressed at the cellular membrane, but it is non-functional [Howard et al 2002]. Lack of KCC3 in the developing nervous system may increase the susceptibility of damaging the fibers migrating across the midline close to the subarachnoid space to form the corpus callosum. As this structure forms during embryogenesis, absence of KCC3 must have phenotypic effects early during neuronal development. The findings in the peripheral nervous system, on the other hand, are progressive and do not suggest any migratory abnormality. The site of maximum damage in the peripheral nervous system appears to be in the nerve roots, where nerve fibers are bathed in cerebrospinal fluid (CSF). This is where the great majority of swollen axons are encountered, along with aberrant regeneration and Schwann cell proliferation [Dupré et al 2003]. KCC3 knockout mice have reduced seizure threshold, deafness, and degeneration in the central and peripheral nervous systems [Boettger et al 2003].