M. Leach

TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype

Mutations in TPM3, encoding Tpm3.12, cause a clinically and histopathologically diverse group of myopathies characterized by muscle weakness. We report two patients with novel de novo Tpm3.12 single glutamic acid deletions at positions ΔE218 and ΔE224, resulting in a significant hypercontractile phenotype with congenital muscle stiffness, rather than weakness, and respiratory failure in one patient.

Novel De Novo Mutations in KIF1A as a Cause of Hereditary Spastic Paraplegia With Progressive Central Nervous System Involvement

Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of disorders characterized by lower extremity spasticity and weakness. Recently, the first de novo mutations in KIF1A were identified in patients with an early-onset severe form of complicated hereditary spastic paraplegia. We report two additional patients with novel de novo mutations in KIF1A, hereby expanding the genetic spectrum of KIF1A-related hereditary spastic paraplegia. Both children presented with spastic paraplegia and additional findings of optic nerve atrophy, structural brain abnormalities, peripheral neuropathy, cognitive/language impairment, and never achieved ambulation. In particular, we highlight the progressive nature of cerebellar involvement as captured on sequential magnetic resonance images (MRIs), thus linking the neurodegenerative and spastic paraplegia phenotypes. Exome sequencing in patient 1 and patient 2 identified novel heterozygous missense mutations in KIF1A at c.902G>A (p.R307Q) and c.595G>A (p.G199 R), respectively. Therefore, our report contributes to expanding the genotypic and phenotypic spectrum of hereditary spastic paraplegia caused by mutations in KIF1A.

English Cross-Cultural Translation and Validation of the Neuromuscular Score: A System for Motor Function Classification in Patients With Neuromuscular Diseases

OBJECTIVE To develop and validate an English version of the Neuromuscular (NM)-Score, a classification for patients with NM diseases in each of the 3 motor function domains: D1, standing and transfers; D2, axial and proximal motor function; and D3, distal motor function. DESIGN Validation survey. SETTING Patients seen at a medical research center between June and September 2013. PARTICIPANTS Consecutive patients (N=42) aged 5 to 19 years with a confirmed or suspected diagnosis of congenital muscular dystrophy. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES An English version of the NM-Score was developed by a 9-person expert panel that assessed its content validity and semantic equivalence. Its concurrent validity was tested against criterion standards (Brooke Scale, Motor Function Measure [MFM], activity limitations for patients with upper and/or lower limb impairments [ACTIVLIM], Jebsen Test, and myometry measurements). Informant agreement between patient/caregiver (P/C)-reported and medical doctor (MD)-reported NM scores was measured by weighted kappa. RESULTS Significant correlation coefficients were found between NM scores and criterion standards. The highest correlations were found between NM-score D1 and MFM score D1 (ρ=-.944, P<.0001), ACTIVLIM (ρ=-.895, P<.0001), and hip abduction strength by myometry (ρ=-.811, P<.0001). Informant agreement between P/C-reported and MD-reported NM scores was high for D1 (κ=.801; 95% confidence interval [CI], .701-.914) but moderate for D2 (κ=.592; 95% CI, .412-.773) and D3 (κ=.485; 95% CI, .290-.680). Correlation coefficients between the NM scores and the criterion standards did not significantly differ between P/C-reported and MD-reported NM scores. CONCLUSIONS Patients and physicians completed the English NM-Score easily and accurately. The English version is a reliable and valid instrument that can be used in clinical practice and research to describe the functional abilities of patients with NM diseases.

Congenital Titinopathy: Comprehensive characterization and pathogenic insights: Congenital Titinopathy

Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder.

Electrical impedance myography in individuals with collagen 6 and laminin α-2 congenital muscular dystrophy: a cross-sectional and 2-year analysis: EIM in COL6 and LAMA2 CMD

Electrical impedance myography (EIM) is a noninvasive electrophysiological technique that characterizes muscle properties through bioimpedance. We compared EIM measurements to function, strength, and disease severity in a population with congenital muscular dystrophy (CMD).

Cytoplasmic body pathology in severe ACTA1-related myopathy in the absence of typical nemaline rods

Mutations in ACTA1 cause a group of myopathies with expanding clinical and histopathological heterogeneity. We describe three patients with severe ACTA1-related myopathy who have muscle fiber cytoplasmic bodies but no classic nemaline rods. Patient 1 is a five-year-old boy who presented at birth with severe weakness and respiratory failure, requiring mechanical ventilation. Whole exome sequencing identified a heterozygous c.282C>A (p.Asn94Lys) ACTA1 mutation. Patients 2 and 3 were twin boys with hypotonia, severe weakness, and respiratory insufficiency at birth requiring mechanical ventilation. Both died at 6 months of age. The same heterozygous c.282C>A (p.Asn94Lys) ACTA1 mutation was identified by whole exome sequencing. We conclude that clinically severe ACTA1-related myopathy can present with muscle morphological findings suggestive of cytoplasmic body myopathy in the absence of definite nemaline rods. The Asn94Lys mutation in skeletal muscle sarcomeric α-actin may be linked to this histological appearance. These novel ACTA1 cases also illustrate the successful application of whole exome sequencing in directly arriving at a candidate genetic diagnosis in patients with unexpected phenotypic and histologic features for a known neuromuscular gene.

G.P.152

Congenital myopathies are a heterogeneous group of non-dystrophic muscle disorders characterized by weakness/hypotonia presenting in infancy. Diagnoses are based on clinical and characteristic pathologic features confirmed with genetic testing. Ophthalmoparesis is a useful but non-specific clinical sign that can be diagnostically helpful if the clinical context is taken into careful consideration. Myosins are fiber-type specific, actin-binding proteins essential for muscle contraction. MYH2 encodes MyHC IIa, predominantly expressed in type 2A fibers. 2 confirmed AD missense mutations have been reported in MYH2 and are associated with a childhood/adult-onset, slowly-progressive inclusion body myopathy with ophthalmoparesis and congenital contractures. 10 recessive MYH2 mutations have been recognized and are characterized by childhood-onset marked external ophthalmoparesis and a mild myopathy. We describe siblings with previously unreported compound heterozygous truncating mutations in MYH2 presenting with decreased fetal movements, congenital onset facial weakness and myopathy without congenital contractures, normal acquisition of motor milestones, marked ophthalmoparesis, and notably rapidly progressive scoliosis requiring spinal fusion in the early teens. While spinal abnormalities are frequently reported in the dominant mutations, it has not been a significant finding in recessive mutations. Severe progressive scoliosis has not been reported in either type/form. Congenital joint contractures are a hallmark feature in patients with dominant MYH2 mutations, yet this is not observed with recessive mutations. These findings indicate that recessive MYH2 mutations should be considered in the differential diagnosis of early-onset ophthalmoparesis, mild myopathy with type I predominance, and progressive scoliosis in the absence of a positive family history or other distinctive biopsy findings.