To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene.Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1.We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features.Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions.

Progressive muscular atrophy

10.1212/wnl.0000000000001269

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Citations (121)

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

Genetics in Medicine (2020)

Ana Töpf Katherine Johnson Adam Bates Lauren Phillips Katherine R. Chao

Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology.Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions.We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation.Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.

Exome

Etiology

Rare disease

Neuromuscular disease

10.1038/s41436-020-0840-3

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Citations (89)

Acute management of a stroke-like episode in MELAS syndrome: What should we know?

eNeurologicalSci (2020)

T. González-Pinto González Javier Almeida Velasco Ana Moreno‐Estébanez Garazi Agirre Beitia Laura Martinez

•Acute management of SLEs differs from usual therapy in classic stroke patients.•IV L-Arginine should be administered urgently in the setting of a SLE.•If mental status is altered, an EEG should be performed to rule out a non-convulsive status.

MELAS syndrome

Stroke

Acute stroke

10.1016/j.ensci.2020.100249

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Citations (5)

20725. LA CLAVE ESTÁ EN LA RESONANCIA MAGNÉTICA: UN CASO DE MENINGITIS POR ARTRITIS REUMATOIDE

Neurology Perspectives (2024)

M. Cortés Rubiales S. Fernández Soberón O. Goyena Morata C. Sifre Peña A. Gamboa Berastegui

10.1016/s2667-0496(24)00944-x

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