Expanding the MYBPC1 phenotypic spectrum: a novel homozygous mutation causes arthrogryposis multiplex congenita.

Arthrogryposis multiplex congenita (AMC) is characterized by heterogeneous nonprogressive multiple joint contractures appearing at birth. We present a consanguineous Israeli-Druze family with several members presenting with AMC. A variable intra-familial phenotype and pected autosomal recessive inheritance prompted molecular diagnosis by whole-exome sequencing. Variant analysis focused on rare homozygous changes, revealed a missense variant in MYBPC1, NM_002465:c.556G>A (p.E286K), affecting the last nucleotide of Exon 8. This novel variant was not observed in the common variant databases and co-segregated as expected within the extended family. MYBPC1 encodes a slow skeletal muscle isoform, essential for muscle contraction. Heterozygous mutations in this gene are associated with distal arthrogryposis types 1b and 2, whereas a homozygous nonsense mutation is implicated in one family with lethal congenital contractural syndrome 4. We present a novel milder MYBPC1 homozygous phenotype.

SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum.

Two unrelated patients, presenting with significant global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) underwent trio whole-exome sequencing. No candidate variant was found in any known genes related to the phenotype. However, crossing the data of the patients illustrated that they both manifested pathogenic variants in the SLC1A4 gene which codes the ASCT1 transporter of serine and other neutral amino acids. The Ashkenazi patient is homozygous for a deleterious missense c.766G>A, p.(E256K) mutation whereas the Ashkenazi-Iraqi patient is compound heterozygous for this mutation and a nonsense c.945delTT, p.(Leu315Hisfs*42) mutation. Structural prediction demonstrates truncation of significant portion of the protein by the nonsense mutation and speculates functional disruption by the missense mutation. Both mutations are extremely rare in general population databases, however, the missense mutation was found in heterozygous mode in 1:100 Jewish Ashkenazi controls suggesting a higher carrier rate among Ashkenazi Jews. We conclude that SLC1A4 is the disease causing gene of a novel neurologic disorder manifesting with significant intellectual disability, severe postnatal microcephaly, spasticity and thin CC. The role of SLC1A4 in the serine transport from astrocytes to neurons suggests a possible pathomechanism for this disease and implies a potential therapeutic approach.

Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin.

BACKGROUND: AIFM1 encodes a mitochondrial flavoprotein with a dual role (NADH oxidoreductase and regulator of apoptosis), which uses riboflavin as a cofactor. Mutations in the X-linked AIFM1 were reported in relation to two main phenotypes: a severe infantile mitochondrial encephalomyopathy and an early-onset axonal sensorimotor neuropathy with hearing loss. In this paper we report two unrelated males harboring AIFM1 mutations (one of which is novel) who display distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. METHODS: For both patients trio whole exome sequencing was performed. Validation and segregation were performed with Sanger sequencing. Following the diagnosis, patients were treated with up to 200 mg riboflavin/day for 12 months. Ataxia was assessed by the ICARS scale at baseline, and 6 and 12 months following treatment. RESULTS: Patient 1 presented at the age of 5 years with auditory neuropathy, followed by progressive ataxia, vermian atrophy and axonal neuropathy. Patient 2 presented at the age of 4.5 years with severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, hyporeflexia and cardiomyopathy. Two deleterious missense mutations were found in the AIFM1 gene: p. Met340Thr mutation located in the FAD dependent oxidoreductase domain and the novel p. Thr141Ile mutation located in a highly conserved DNA binding motif. Ataxia score, decreased by 39% in patient 1 and 20% in patient 2 following 12 months of treatment. CONCLUSION: AIFM1 mutations cause childhood cerebellar ataxia, which may be partially treatable in some patients with high dose riboflavin.