Very severe spinal muscular atrophy: Type 0 with Dandy-Walker variant.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. In addition to the three classical SMA types, a new form known as type 0 with intrauterine onset, profound hypotonia and a progressive and early fatal course has been described. Herein we report a case of type 0 SMA with a Dandy Walker variant anomaly, which has not hitherto been reported in the world literature.

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of anterior horn cells of the spinal cord leading to progressive symmetrical weakness and atrophy of the proximal muscles. In addition to classical SMA types (type 1, 2 and 3) a new form of SMA called type 0 with intrauterine onset and hypotonia, a progressive and early fatal course has been described.[1234] Here in we report one such case of SMA type 0 in combination with a Dandy-Walker variant. This association to the best of our knowledge has not been reported earlier.

Case Report

Baby S was a second born male infant to non-consanguineous parents, 28-year-old father and 22-year-old mother. First child was a healthy baby girl. The pregnancy was unremarkable but the mother reported decreased fetal movements from 30 weeks of gestation. There was no polyhydroamnios. Antenatal ultrasound revealed cisterna magna communicating with the fourth ventricle through the cerebellar hemisphere: findings consistent with a Dandy-Walker variant. Baby was born by spontaneous vaginal delivery at 39 weeks of gestation, weighing 2.75 kg. The cry was weak and the baby needed bag and mask ventilation. He was noted to be hypotonic with poor spontaneous efforts and was intubated and shifted to NICU and mechanically ventilated. Extreme hypotonia of limbs was noted with a strikingly alert look. There were no spontaneous movements of limbs and the deep tendon reflexes were absent. No seizures were noted and there was no clinical or lab evidence suggestive of hypoxic-ischemic injury to other organ systems. The alert look was in contrast to the marked hypotonia and absent spontaneous muscle activity. The infant continued to be ventilator dependent. A diagnosis of SMA was considered and confirmed on molecular genetic analysis which revealed the homozygous deletion of exon 7 of SMN1 gene. A post natal CT scan revealed partial vermian hypoplasia with partial obstruction to the fourth ventricle but no enlargement of posterior fossa: findings consistent with Dandy-Walker variant [Figure 1]. The baby died immediately after the mechanical ventilation was discontinued on day 19 of life at the request of the parents.

Figure 1

CT scan showing partial vermian hypoplasia with partial obstruction to 4th ventricle but no posterior fossa enlargement: Findings suggestive of Dandy Walker variant

Discussion

Very severe SMA (type 0) reportedly presents with reduced fetal movements in utero, profound hypotonia, severe asphyxia and respiratory insufficiency at birth warranting resuscitation and mechanical ventilatory support. An alert look in sharp contrast to the severe hypotonia has been uniformly observed. All reported cases have been ventilator dependent and died in the neonatal period after the support was withdrawn, generally on the request of the parents.[24] Genetic studies have revealed homozygous deletions of exon 7 and 8 of the SMN gene in these infants making the diagnosis of SMA possible.[4] The index case too had an antenatal onset with history of decreased fetal movements from 30 weeks of gestation, severe asphyxia needing resuscitation and mechanical ventilation, profound hypotonia and a striking alert look of the baby. Like other cases reported till date our infant was also ventilator dependent and died on day 19 after the ventilator support was withdrawn at the request of the parents once the diagnosis was confirmed by molecular analysis showing homozygous deletion of exon 7 of SMN1 gene.

The most severe type of SMA presents itself at birth or in the early days of life which may be difficult for primary care providers or pediatricians to diagnose. Proper diagnosis of this disorder needs a high index of suspicion and understanding of clinical signs and symptoms. SMA should be kept in mind in the differential diagnosis for unexplained severe generalized hypotonia and severe respiratory distress immediately after birth in the neonates, notably in patients with a bright expression and alert look. To date, it is not known with certainty whether this subgroup represents a distinct entity or is merely the severe end of the classical SMA type 1. Dubowitz explains that from a classification point of view, the more severe cases with prenatal onset and intrauterine death or with severe asphyxia at birth and early neonatal death fit into the category of “very severe” SMA (type 0) as an extension to previous severe SMA type 1.[1]

There are several reports of SMA with additional features (SMA plus), including pontocerebellar hypoplasia,[5] diaphragmatic paralysis[6] and Dandy-Walker complex.[7] The report on SMA in combination with Dandy-Walker complex was in two siblings aged 23 and 25 years who were symptomatic since the age of 10 years with progressive, symmetrical distal muscle weakness and bilateral anterior polar cataracts diagnosed at the age of 9-11 months. The molecular genetic analysis revealed homozygous deletions of exon 7 and 8 of the SMN gene. In the present case SMA type 0 was seen in combination with Dandy-Walker variant. A Dandy-Walker variant is a less severe posterior fossa anomaly than the classical Dandy-Walker malformation and is considered being on the lesser end of the disease spectrum in the Dandy-Walker continuum. There is usually partial vermian hypoplasia and partial obstruction of the fourth ventricle but without enlargement of the posterior fossa: as observed in the present case.

To conclude, our case represents an unusual combination of severe spinal muscular atrophy (type 0) and Dandy-Walker variant hitherto not reported in the literature.