Infantile spinal muscular atrophy with respiratory distress, type 1 (SMARD1)

Rare neuromuscular disorder with fatal progression due to diaphragmatic paralysis. SMARD is a clinically and genetically heterogeneous condition. The following information refers only to SMARD1.

Inheritance: autosomal recessive
Incidence: unknown
Prevalence: approx. 1% of all cases with infantile SMA

Pathophysiology:

• Degeneration of alpha motor neurons, predominantly in the upper spinal cord.
• Functions of gene product (see below) not yet identified. Presumably, the gene product is involved in RNA processing in alpha motor neurons. It may also play a role in myocytes.

Clinical features:

• Intrauterine growth retardation, prematurity, weak cry and generalized low muscle tone as potential early signs.
• 1 - 6 months (usually not connatal): progressive, symmetric paralysis of diaphragm, requiring ventilatory support, relative sparing of intercostal muscles.
• Progressive atrophy of predominantly distal limb muscles; legs more affected than arms, joint contractures may be present .
• Sensory and autonomous nervous system involvement in some cases (hypoesthesia, excessive sweating, constipation, cardiac arrhythmias, reflux nephropathy, etc.)
• Electrophysiology, biopsy and laboratory analysis show results comparable to those in SMA1 (including normal or slightly elevated CK).
• Survival time often ≤ 1 year. Longest reported survival time: 11 years.

Genetic cause:

• Mutations in IGHMBP2 gene on 11q13.2-q13.4 (immunoglobulin μ-binding protein 2).

Available diagnosis:

• Clinical:
• Diaphragmatic paralysis (chest x-ray), progressive muscular atrophies and joint contractures, predominantly distal.
• Molecular genetic testing:
• Exclusion of homozygous SMN1 deletion.
• 
  

  Type	Gene / Protein	Exons	Mutations	Test	Method of Analysis
  SMARD1	IGHMBP2 / immunoglobulin μ-binding protein 2	15	approx. 20%	yes	Sequencing

• (With two or more affected and unaffected persons within the same family, linkage analysis with regard to the IGHMBP2 locus can be attempted prior to sequencing.)
• Genotype-phenotype correlation:
• No clear data yet.
• Prenatal testing:
• By direct gene sequencing, provided an IGHMBP2 mutation has been identified in the index patient.

Database:

• SMARD1: OMIM 604320
• IGHMBP2 gene: OMIM 600502

Contact: Raoul Heller, Jutta Becker, Brunhilde Wirth (see Staff)

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