Infantile-onset spinal muscular atrophy with respiratory distress-1 diagnosed in a 20-year-old man

doi:10.1016/j.nmd.2011.02.005

Neuromuscular Disorders

Volume 21, Issue 5, May 2011, Pages 353-355

https://doi.org/10.1016/j.nmd.2011.02.005 Get rights and content

Abstract

Spinal muscular atrophy with respiratory distress (SMARD1) presents within the first 13 months of age with low birth weight, progressive length dependent motor neuropathy, and respiratory failure from diaphragmatic paralysis. SMARD1 is caused by mutations in IGHMBP2, encoding the immunoglobulin μ-binding protein 2. Because of the severity of the disorder, many infantile-onset SMARD1 patients do not live past the first decade of life. This report documents the clinical course of a 20-year-old man diagnosed with SMARD1.

Introduction

Spinal muscular atrophy with respiratory distress (SMARD1; MIM#604320) is a rare infantile neuromuscular disorder that presents with diaphragmatic paralysis and a length-dependent polyneuropathy [1], [2]. Also known as autosomal-recessive distal spinal muscular atrophy 1 or distal hereditary motor neuronopathy type 6, this disorder is caused by mutations in the IGHMBP2 gene, which resides on chromosome 11q13.3 and encodes the immunoglobulin μ-binding protein 2 [3]. A member of the DEXDc DEAD-like superfamily of DNA/RNA helicases, IGHMBP2 is thought to function in transcriptional activation and/or associates with pre-messenger RNA (mRNA) splicing complexes [4].

Initially described as an unusual variant of spinal muscular atrophy (SMA; MIM#600354), SMARD1 has now been recognized to have its own unique phenotype. Features include decreased fetal movements, oligohydramnios, low birth weight, distal muscular atrophy, foot/finger deformities, and diaphragmatic dysfunction resulting in the need for ventilation prior to 13 months of age [2], [5]. The numerous individuals reported with SMARD1 [2], [3], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14] presented in a fairly homogenous fashion. A similar phenotype is found in the neuromuscular degeneration (nmd) mouse, a spontaneously-generated model with mutations in Ighmbp2. These mice present with a motor neuron disease that is fatal by 3–4 months of age [15]. Interestingly, neuron-specific rescue of Ighmbp2 expression revealed that nmd mice also exhibit a skeletal myopathy and dilated cardiomyopathy [4], [9], [16]. The cardiomyopathy has not been seen in humans to date. Most reported SMARD1 patients have been under the age of 10 and so the disease course and prognosis for adolescence and young adulthood have not been documented. We present a recently diagnosed 20 year-old male with infantile-onset SMARD1 requiring ventilation since 4 months of age.

Section snippets

Case report

A 20 year-old male of non-consanguineous parentage presented to the NIH Undiagnosed Diseases Program with a history of infantile-onset distal weakness, right hemi-diaphragmatic paralysis, and ventilator dependence. In childhood, he developed a length-dependent progressive sensory-motor neuropathy associated with loss of sensation, muscular denervation and atrophy. He has remained ventilator dependent since age 4 months and had no functional motor control except for facial expression, shoulder

Discussion

SMARD1 is an autosomal-recessive neuromuscular disorder due to mutations in IGHMBP2. This protein is thought to be involved in transcriptional activation and pre-mRNA processing [9], [15]. In most cases, alteration of IGHMBP2 function results in infantile-onset of distal weakness and respiratory failure requiring ventilatory support, although some cases of juvenile-onset SMARD1 have been reported [10]. To date, most cases of infantile-onset SMARD1 have resulted in lethality in the first decade

Acknowledgements

The staff of the Undiagnosed Diseases Program were all instrumental in this work and we thank them for their help and efforts. Additional thanks to Barrington Burnet for critical review of the manuscript. We would like to acknowledge the hard work and generosity of the patient, his family, and his caregivers. TMP, DA, GG, CJT, CT, and WAG were supported by the NIH Undiagnosed Diseases Program, National Institutes of Health.

References (16)

V.C. Wong et al.
Mutation of gene in spinal muscular atrophy respiratory distress type I
Pediatr Neurol
(2006)
S. Joseph et al.
Interfamilial phenotypic heterogeneity in SMARD1
Neuromuscul Disord
(2009)
G.A. Cox et al.
Identification of the mouse neuromuscular degeneration gene and mapping of a second site suppressor allele
Neuron
(1998)
R.B. Mellins et al.
Respiratory distress as the initial manifestation of Werdnig-Hoffmann disease
Pediatrics
(1974)
A.M. Kaindl et al.
Spinal muscular atrophy with respiratory distress type 1 (SMARD1)
J Child Neurol
(2008)
K. Grohmann et al.
Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1
Nat Genet
(2001)
T.P. Maddatu et al.
Transgenic rescue of neurogenic atrophy in the nmd mouse reveals a role for Ighmbp2 in dilated cardiomyopathy
Hum Mol Genet
(2004)
M. Pitt et al.
Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1
Brain
(2003)

There are more references available in the full text version of this article.

Cited by (23)

Models for IGHMBP2-associated diseases: an overview and a roadmap for the future
2021, Neuromuscular Disorders
Models are practical tools with which to establish the basic aspects of a diseases. They allow systematic research into the significance of mutations, of cellular and molecular pathomechanisms, of therapeutic options and of functions of diseases associated proteins. Thus, disease models are an integral part of the study of enigmatic proteins such as immunoglobulin mu-binding protein 2 (IGHMBP2). IGHMBP2 has been well defined as a helicase, however there is little known about its role in cellular processes. Notably, it is unclear why changes in such an abundant protein lead to specific neuronal disorders including spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S). SMARD1 is caused by a loss of motor neurons in the spinal cord that results in muscle atrophy and is accompanied by rapid respiratory failure. In contrast, CMT2S manifests as a severe neuropathy, but typically without critical breathing problems. Here, we present the clinical manifestation of IGHMBP2 mutations, function of protein and models that may be used for the study of IGHMBP2-associated disorders. We highlight the strengths and weaknesses of specific models and discuss the orthologs of IGHMBP2 that are found in different systems with regard to their similarity to human IGHMBP2.
Combined Genome Sequencing and RNA Analysis Reveals and Characterizes a Deep Intronic Variant in IGHMBP2 in a Patient With Spinal Muscular Atrophy With Respiratory Distress Type 1
2021, Pediatric Neurology
Pathogenic variants in the IGHMBP2 gene cause recessive spinal motor neuropathies of variable phenotype, including a predominantly distal motor impairment of Charcot-Marie-Tooth type 2S and the more severe condition of spinal muscular atrophy with respiratory distress type 1 in which infantile respiratory failure predominates.
We describe the first reported case of spinal muscular atrophy with respiratory distress type 1 caused by a novel deep intronic variant in IGHMBP2 (NM_002180c.712-610A>G).
The variant was detected by whole genome sequencing. Reverse transcription–polymerase chain reaction and complimentary DNA sequencing were used to characterize the impact of the novel variant.
This report illustrates the utility in clinical practice of genome sequencing and RNA analysis, compared with exome sequencing alone.
Spinal muscular atrophy with respiratory distress type 1: A multicenter retrospective study
2019, Neuromuscular Disorders
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder characterized by progressive motor and respiratory decline during the first year of life. Early and late-onset cases have recently been reported, although not meeting the established diagnostic criteria, these cases have been genotyped. We thus conducted a national multicenter observational retrospective study to determine the prognosis of children with SMARD1 according to their phenotype. We recorded all known French pediatric cases with mutations identified on the immunoglobulin μ-binding protein 2 gene and the presence of respiratory symptoms. Thirty centers provided 22 observations. A diaphragmatic palsy was diagnosed 1.5 months (p = 0.02) after first respiratory symptoms, and hypotonia preceded areflexia by 4 months (p = 0.02). Early onset of symptoms leading to specialist consultation before the age of 3 months was associated with a significantly worse prognosis (p < 0.01). Among the 6 patients who were still alive, all were tracheostomized. Only one case survived beyond 2 years without artificial ventilation. The remaining patients died at a median age of 7 months. Our results may help pediatricians to provide medical information to parents and improve the decision-making process of setting up life support.
Charcot Marie Tooth disease type 2S with late onset diaphragmatic weakness: An atypical case
2018, Neuromuscular Disorders
Immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) mutations are associated with partial continuum between two extremes of rapidly lethal disorder of spinal muscular atrophy with respiratory distress type 1 (SMARD1), with infantile axonal neuropathy, diaphragmatic weakness and commonly death before 1 year of age, and Charcot-Marie-Tooth disease (CMT) type 2S with slowly progressive weakness and sensory loss but no significant respiratory compromise. We present an atypical case of CMT2S. A 9 month old boy presented with bilateral feet deformities and axonal neuropathy. Genetic testing revealed two heterozygous variants in the IGHMBP2 gene: c.1156 T > C p.(Trp386Arg) in exon 8 and c.2747G > A p.(Cys916Tyr) in exon 14, that were inherited from his father and mother respectively. At 9 years, he developed diaphragmatic weakness, following which he was established on non-invasive ventilation. Our case emphasizes the importance of life long respiratory surveillance for patients with CMT2S and expands the phenotype of this condition.
IGHMBP2-related clinical and genetic features in a cohort of Chinese Charcot–Marie–Tooth disease type 2 patients
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IGHMBP2 mutations had been exclusively associated with spinal muscular atrophy with respiratory distress type I. However, increasing AR-CMT2S cases without respiratory failure caused by IGHMBP2 mutations have been reported in the past two years. We detected IGHMBP2 mutations in a cohort of Chinese CMT2 patients using genes panel testing, polymerase chain reaction and Sanger sequencing. We found four families with autosomal recessive IGHMBP2 mutations, and the frequency of IGHMBP2 mutations is 6.5% in CMT2 without dominant inheritance. We detected a homozygous variant c.1235 + 3A > G in Family 1, compound heterozygous variants c.1737C > A and c.2597_2598delAG in Family 2, compound heterozygous variants c.1489G > A and c.2356delG in Family 3, compound heterozygous variants c.1909C > T and c.1061-2A > G in Family 4. According to the standards and guidelines of the American College of Medical Genetics and Genomics, all the above variants were classified as pathogenic. Four mutations, c.1489G > A, c.2356delG, c.2597_2598delAG and c.1061-2A > G, are reported for the first time. The novel splice acceptor site mutation c.1061-2A > G resulted in deletion of 175 bp, and it was predicted to lead to a frameshift after codon 354 with a premature termination at codon 364. In conclusion, mutation screening of IGHMBP2 should be especially considered in AR-CMT2 and sporadic CMT2 patients.
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Case reportInfantile-onset spinal muscular atrophy with respiratory distress-1 diagnosed in a 20-year-old man

Abstract

Introduction

Section snippets

Case report

Discussion

Acknowledgements

Pediatr Neurol

Neuromuscul Disord

Neuron

Respiratory distress as the initial manifestation of Werdnig-Hoffmann disease

Pediatrics

Spinal muscular atrophy with respiratory distress type 1 (SMARD1)

J Child Neurol

Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1

Nat Genet

Transgenic rescue of neurogenic atrophy in the nmd mouse reveals a role for Ighmbp2 in dilated cardiomyopathy

Hum Mol Genet

Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1

Brain

Case report
Infantile-onset spinal muscular atrophy with respiratory distress-1 diagnosed in a 20-year-old man