Spinal muscular atrophy with respiratory distress type 1 (SMARD1) Report of a Spanish case with extended clinicopathological follow-up

Abstract

Background: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a clinically and genetically distinct and uncommon variant of SMA that results from irreversible degeneration of α-motor neurons in the anterior horns of the spinal cord and in ganglion cells on the spinal root ganglia.

Aims: To describe the clinical, electrophysiological, neuropathological, and genetic findings, at different stages from birth to death, of a Spanish child diagnosed with SMARD1.

Patient and methods: We report the case of a 3-monthold girl with severe respiratory insufficiency and, later, intense hypotonia. Paraclinical tests included biochemistry, chest X-ray, and electrophysiological studies, among others. Muscle and nerve biopsies were performed at 5 and 10 months and studied under light and electron microscopy. Post-mortem examination and genetic investigations were performed.

Results: Pre- and post-mortem histopathological findings demonstrated the disease progression over time. Muscle biopsy at 5 months of age was normal, however a marked neurogenic atrophy was present in post-mortem samples. Peripheral motor and sensory nerves were severely involved likely due to a primary axonal disorder. Automatic sequencing of IGHMBP2 revealed a compound heterozygous mutation.

Conclusions: The diagnosis of SMARD1 should be considered in children with early respiratory insufficiency or in cases of atypical SMA. Direct sequencing of the IGHMBP2 gene should be performed.

Figure 1.. A: Semithin section of sural nerve biopsy at 5 months of age showing marked reduction of myelinated fiber density and endoneurial fibrosis, without onion bulbs, axonal sprouting, or inflammatory infiltrates. (Toluidine blue 200×). B: Demyelinated axons and Schwann cells arranged into bands of Büngner under electron microscopy examination of the sural nerve sample at 5 months. C: Muscle biopsy at 10 months of age (H & E 200×). Note marked peri and endomysial fibrosis and fatty infiltration with groups of small fibers and scattered hypertrophic fibers. D: NADH staining showing atrophic fibers with increased oxidative activity (NADH 200x).

Figure 2.. Immunohistochemical expression of developmental (dMHC), slow (sMHC), and fast (fMHC) myosin heavy chains in muscle biopsy at 10 months of age showing features of immature fetal phenotype. A: Developmental myosin predominates in atrophic and a few hypertrophic fibers (dMHC 200×). B: Slow HC myosin: hypertrophic fibers are characterized by their predominant expression; atrophic fibers also express slow HC. C: Fast MHC: atrophic fibers.

Figure 3.. Post-mortem findings: A: Anterior horn of the spinal cord showing atrophy and significant reduction of motor neurons (H & E 200×). B: The remaining neurons presented chromatolysis and pyknosis (H & E 400×). C: Dorsal root ganglia with marked neuronal loss and abundant clusters of satellite cells’ nuclei (Nageotte nodules) (H & E 200×). D; E: Semithin sections. Remarkable nerve damage in sural and sciatic nerves, respectively, consisting of massive loss of myelinated fibers without signs of axonal regeneration or remyelination (Toluidine blue 100×). F: Severe fiber atrophy, fibrosis, and infiltration of diaphragmatic muscle sample (H & E 200×).