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P 856. Andermann’s Syndrome—Symptom Complex of Agenesis of the Corpus Callosum and Motor–Sensory Neuropathy
30 October 2018 (online)
Background: Andermann’s syndrome is a rare autosomal recessive disorder due to pathogenic variants in K+–Cl− cotransporter 3 (KCC3). Patients suffer from neurodegeneration, peripheral polyneuropathy, and agenesis of the corpus callosum. We present two sisters with typical symptoms.
Methods: The parents are consanguineous; both of them and the two brothers are not affected.
Patient 1 (girl, 12 years): Development: she was able to sit at the age of 2 years, to walk at 4 years, urinary continence at 5 years, and first words at 2.5 years with persistent speech delay. While getting older, she progressively lost skills: incontinence at 6 years of age, inability to walk and stand at 10 years, progressive psychomotor retardation. She needs increasingly more help in daily life. On examination, we saw prominent distal muscular atrophy with limb weakness, paresis of finger extension, pes equinus, neuromuscular scoliosis, and absent reflexes. The patient is dystrophic (weight <3P, length 10P) with relative macrocephalus (85P).
Patient 2 (girl, 6 years): Comparable to her sister, she reached the milestones of development late. On examination, she can ambulate freely and is able to speak a few words, and she is more independent in daily life but shows significant psychomotor retardation. She has pes equinus on both sides, in combination with pes planus on the right and clubfoot on the left side and absent reflexes. She presents with short stature (length 3P, weight 50P) and head circumference on the 75th percentile.
Diagnostic Findings: We performed cranial magnetic resonance imaging and both sisters have a complete agenesis of the corpus callosum without further pathologies. On electrophysiologic testing, both sisters have pathologic results consistent with a severe polyneuropathy. We found increased protein in the cerebrospinal fluid, no signs of a metabolic defect, and normal additional screening tests (abdominal ultrasound, echocardiography, fundoscopy, and hearing test). Both patients’ EEG showed a slowed background activity.
Molecular genetic testing confirmed a homozygous pathogenic variant in the SLC12A6 gene.
Conclusion: Andermann’s syndrome, also called agenesis of corpus callosum and peripheral neuropathy, is caused by mutations in the SCL12A6 gene on chromosome 15q13-q15 coding for the cotransporter KCC3. In addition to other tissues, KCC3 is expressed in neurons and glia cells and plays a role in K/Cl homeostasis important for cell volume regulation but also cell proliferation. KCC3 knockout mice have degeneration in the central and peripheral nervous system, reduced seizure threshold and deafness.
Andermann’s syndrome occurs with an incidence of 1:2,000 in the French–Canadian population of Quebec due to a founder mutation. Beyond that only sporadic cases have been published. Our patients have a homozygous mutation known from two siblings with compound heterozygote mutations and typical symptoms of Andermann’s syndrome. The mutation is located in an essential splice-site region. The combination of peripheral polyneuropathy and agenesis of the corpus callosum should lead to the differential diagnosis of Andermann’s syndrome.