Heterogeneity in spinal muscular atrophy with respiratory distress type 1.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a clinically heterogeneous disorder linked to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. Most infants with SMARD1 present between six weeks and six months of age with respiratory distress secondary to diaphragmatic weakness and progressive distal weakness. Sensory and autonomic dysfunctions sometimes accompany the motor weakness. This report describes a male infant with genetically confirmed SMARD1 presenting with onset of disease in the first two weeks of life with respiratory compromise and urinary retention, which has not been reported before and adds to the phenotypic variability of SMARD 1.

Introduction

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare infantile form of anterior horn cell disease. It is an autosomal recessive disorder attributed to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene located on chromosome 11q13-q21.[1] SMARD1 is characterized by intrauterine growth retardation, weak cry, distal muscle weakness, contractures, and respiratory failure due to early diaphragmatic weakness leading to ventilator dependence. Sensory and autonomic nerve dysfunction accompany motor weakness.[2-5]

Cohort studies report normal neurological and pulmonary assessment at birth and during the first few weeks of life, with the onset of respiratory failure between one and six months of age in infants with SMARD1. No mutations were found among patients with onset of respiratory distress below one month of age, suggesting that SMARD phenotypes with an early onset are not linked to the IGHMBP2 gene.[2-5]

We report the case of a male child born to healthy, consanguineous parents with homozygous IGHMBP2 gene mutations, presenting with respiratory distress and urinary retention in the first two weeks of life, which has not been reported before in SMARD1.

Case Report

The proband was a male infant of Indian parents who were second cousins, born prematurely at 35 weeks gestation. The mother had chicken pox around 13 weeks of pregnancy. Decreased fetal movements and restriction of growth complicated the pregnancy. Antenatal scans showed normal liquor volume and fetal morphology. The baby had a breech presentation and was delivered via caesarean section. He needed minimal resuscitation and was admitted to the neonatal unit for feeding support. He was symmetrically small for his gestational age. Birth weight was 1.6 kg (0.4th-2nd centile) and head circumference 29 cm (0.4th-2nd centile). On examination, the newborn was appropriate for gestational age.

A previous pregnancy had resulted in a stillborn male baby delivered at term; antenatal scan revealed restriction of intrauterine growth but was otherwise normal. The parents had declined a post mortem examination and no genetic or metabolic tests had been performed. In the family, three other female siblings remain alive and well.

At two weeks of age, he developed respiratory distress and poor feeding over two days, needing intubation and ventilation due to deteriorating respiratory function. Subsequently, multiple attempts at extubation failed due to ineffective response to nasal continuous positive airway pressure (CPAP) therapy. He remained ventilator dependent due to inadequate and paradoxical breathing.

On examination, he had marked axial hypotonia with good peripheral tone and antigravity movements of the arms and absence of contractures. Deep tendon reflexes were difficult to elicit and cranial nerves were not involved. There was no facial weakness. Tongue fasciculations were absent. He had bilateral overlapping of toes, fifth over the fourth, and undescended testes. Direct laryngotracheobronchoscopy, eye examination, and hearing assessment were normal. Pyridostigmine up to 10 mg/kg/day was tried for three weeks but with no benefit. Ultrasound scan of the chest showed sluggish diaphragmatic movement but no paradoxical motion.

The clinical course was further complicated by seizures requiring phenobarbitone. Electroencephalogram showed low-amplitude background activity.

Nerve conduction studies showed severe sensorimotor axonal neuropathy. Electromyography (EMG) study was unremarkable. Molecular genetic tests for SMN 1 gene, Prader-Willi syndrome, myotonic dystrophy type 1, and Charcot-Marie-Tooth neuropathy (PMP22, MPZ, and GJB1 genes) identified no mutations. Other investigations giving normal results included serum creatinine kinase, ammonia, plasma and cerebrospinal fluid (CSF) lactate, urinary organic acids, plasma and urinary amino acids, acetylcholine receptor antibodies, plasma very-long-chain fatty acids, 7-dehydrocholesterol, acylcarnitine, transferrin isoelectric focusing, white cell enzymes, mitochondrial DNA mutation screen, TORCH screen [TORCH: toxoplasma, rubella, cytomegalovirus (CMV), and herpes simplex virus (HSV)], and cerebral and spinal magnetic resonance imaging.

Muscle biopsy showed atrophic changes affecting type 1 and 2 fibers with no fiber type grouping. Respiratory chain enzyme analysis was normal. Sural nerve biopsy was performed but unfortunately no nerve tissue could be identified on histopathology examination.

At one month of age, he started having problems with intermittent urinary retention requiring catheterization. His renal tract ultrasound scan was normal.

By two months of age, he had developed profound weakness and wasting of muscles, particularly in the distal limbs and contractures around the knees and elbows. Intravenous access became difficult, and he deteriorated with frequent chest infections requiring high levels of ventilation. Attempts to wean him off the ventilator remained unsuccessful. A decision was made with the parents, not to escalate treatment in the case of cardiac arrest. The patient died at four months of age, desaturating and becoming bradycardic while attached to the ventilator.

Sequencing of the IGHMBP2 gene revealed a homozygous c.455T > C (p.Leu152Pro) mutation, confirming a diagnosis of SMARD1 after his death. Both parents were later established to be carriers of the IGHMBP2 gene mutation.

The family history revealed multiple consanguineous marriages in the generation of the parents, but no other couples had affected children. The maternal great-grandmother had had six healthy children in addition to seven others who died between the ages of 0 and 4 years. These children were described as having been weak, like our case, but no diagnosis was confirmed. The maternal grandparents and great-grandparents were reported not to be related prior to marriage, making it less likely that these children had the same autosomal recessive disorder as our patient.

Discussion

SMARD1 is clinically and genetically distinct from spinal muscular atrophy type 1 (SMA1). Both of these diseases involve degeneration of the anterior horn cells in the spinal cord resulting in progressive weakness and wasting of muscle.[2]

In SMA type 1 (Werdnig-Hoffman disease), due to a deletion or mutation of the SMN1 gene on chromosome 5q, infants become floppy due to weakness of the proximal limb muscles before progressing to respiratory failure due to paralysis of the intercostal muscles. In SMARD1, early respiratory distress is due to involvement of the diaphragm, which manifests prior to distal muscle weakness.[6]

In 2003, Pitt et al. proposed diagnostic criteria for SMARD1 based on clinical, histopathological, and electrophysiological findings in 13 patients with a diagnosis of SMARD1. The clinical criteria included low birth weight, onset of symptoms within three months, unilateral or bilateral diaphragmatic weakness, ventilator dependence within one month of onset, and absence of dysmorphology or other conditions. The histopathological criteria included reduced myelinated fiber size without evidence of regeneration or demyelination on sural nerve biopsy, and electrophysiological criteria were evidence of distal denervation and severe slowing of conduction in one or more nerves (motor or sensory).[4]

The hallmark clinical feature described in the studies of Guenther (2007), Maystadt (2004), Grohmann (2003), and Pitt (2003) was respiratory failure presenting between six weeks and six months of age, representing the most important single criterion indicting the likelihood of mutation in the IGHMBP2 gene. Additional clinical features reported included involvement of the autonomic nervous system with excessive sweating, constipation, bladder incontinence, and cardiac arrhythmia.[2-57]

A few reports describe survival into the second decade, but after infancy, all cases required long term ventilatory support.[389]

Our case fulfils the diagnostic criteria established in the previous studies, except that respiratory compromise presented earlier at two weeks of age. This is also the first case reported with urinary retention; the previously reported cases had bladder incontinence due to autonomic involvement.[23]

This case illustrates that SMARD1 phenotype may be broader than previously appreciated and early presentation does not rule out mutations in the IGHMBP2 gene. SMARD1 should therefore be considered in infants presenting with hypotonia, distal weakness, and early-onset respiratory failure to establish an early diagnosis in view of the poor prognosis.