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Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1
Matthew Pitt1, Henry Houlden, Jean Jacobs
1Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children NHS Trust, London, UK. pittm@gosh.nhs.uk
Insights
Mutations in the IGHMBP2 gene are linked to early-onset diaphragmatic palsy and progressive neuropathy in infants. This discovery broadens the diagnostic scope for severe infantile neuropathies and spinal muscular atrophy with respiratory distress.
Area of Science:
- Genetics and Neurology
- Molecular Biology
Background:
- Early-onset diaphragmatic palsy and progressive neuropathy present diagnostic challenges.
- Spinal muscular atrophy with respiratory distress type 1 (SMA-RD1) shares some clinical features.
Observation:
- A cohort of 13 infants with early-onset diaphragmatic palsy and neuropathy was studied.
- Eight patients tested had mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene.
- Clinical, neurophysiological, and histopathological findings suggested shared characteristics.
Findings:
- IGHMBP2 gene mutations were identified in 8/8 tested patients, including homozygous, compound heterozygous, and heterozygous cases.
- Diagnostic criteria were developed, highlighting early respiratory compromise, low birth weight, slow nerve conduction, and reduced myelinated fibers.
- One patient showed no SMA evidence in spinal cord histology, suggesting a distinct condition.
Implications:
- The findings necessitate expanding genetic testing for IGHMBP2 mutations in infants with severe infantile neuropathy and SMA-RD1.
- Genetic and clinical heterogeneity exists, suggesting other genes may cause similar phenotypes.
- Further research into IGHMBP2 function and related genes is crucial for understanding these rare disorders.
Abstract:
A group of 13 patients with early onset diaphragmatic palsy in association with a progressive neuropathy is presented. All eight of those tested were found to have mutations in the same gene encoding the immunoglobulin mu-binding protein 2 (IGHMBP2) in patients with spinal muscular atrophy (SMA) with respiratory distress type 1. Six out of these eight patients had either homozygous or compound heterozygous mutations, and two had only a single heterozygous mutation. Detailed analysis of the clinical picture and the neurophysiological and histopathological findings indicated that these patients shared similar characteristics, which were further developed as a set of diagnostic criteria. Some of the most striking of these were early onset of respiratory compromise, a markedly low birth weight, very slow motor nerve conduction velocities and a general decrease in the size of myelinated fibres on sural nerve biopsy. Extensive histological examination of the spinal cord in one patient failed to find any evidence of an SMA. Four out of the five not tested genetically were positive for all diagnostic criteria. None of the cases of early onset neuropathies or spinal muscular atrophies with early respiratory failure reviewed in the literature shares the exact characteristics, but many do have very close similarities. Their classification varies, but the discovery of mutations in IGHMBP2 in cases that are variously classified as SMA plus or severe infantile neuropathy with respiratory distress points to a need for the search for this genetic defect to be widened to include both groups. The fact that we identified other, similar cases of neuropathy and early respiratory failure with and without IGHMBP2 mutations suggests genetic as well as clinical heterogeneity in these infants. It is possible that infants that do not have mutations in the IGHMBP2 gene will be found to have mutations in a similar functioning gene.
