X-linked myotubular myopathy (XLMTM; MIM# 310400) is a severe congenital muscle disorder caused by mutations in the MTM1 gene. It is characterised by severe hypotonia and generalised muscle weakness in affected males, and is generally a fatal disorder in the neonatal period and early infancy.
Male twins were delivered vaginally at 33 + 4 weeks gestation following onset of preterm labour at a private hospital. Twin 1 was born by vaginal delivery with cephalic presentation; there had been a non-reassuring CTG with a fetal bradycardia. His APGAR scores were 1-3-5 at 1, 5 and 10 min, respectively. He was intubated and resuscitated with two boluses of normal saline for signs and symptoms of shock secondary to extensive bilateral cephalhaematomas. Twin 2 was born vaginally as a footling breech presentation. His APGAR scores were 1-5-5 at 1, 5 and 10 min, respectively. He required resuscitation at birth with intubation and a normal saline bolus because of signs and symptoms of shock as a result of extensive bilateral cephalhaematomas. He also sustained a fractured left femur and right humerus. The preliminary diagnosis at the time of request for retrieval was hypoxic ischaemic encephalopathy.
Twin 1 was administered surfactant prior to transfer to our neonatal intensive care unit. On admission, he was managed with a transfusion of packed red blood cells (PRBCs) for ongoing evidence of shock secondary to blood loss. The coagulation profile was normal. On examination, he displayed marked hypotonia, an absent gag reflex and decreased overall activity. Seizures were noted on amplitude electroencephalogram monitoring and were treated with phenobarbitone (one dose), after which no further seizures were observed. Cranial magnetic resonance imaging (MRI) was performed on day 5 of life and revealed large bilateral subdural hygromas, the cause of which was unclear but may have possibly been secondary to subdural haemorrhages. There was no evidence of hypoxic ischaemic changes.
On admission to the neonatal intensive care unit, twin 2 was managed with PRBCs, fresh frozen plasma, platelets and inotropes for signs and symptoms of shock from extensive blood loss because of the bilateral cephalhaematomas, fractured left femur and right humerus. On examination, he also displayed marked hypotonia, absent gag reflex, decreased overall activity and absent deep tendon reflexes. The initial MRI brain of twin 2 also showed large bilateral cephalhematomas and large subdural hygromas/effusions. As with his sibling, the underlying brain appeared normal with no evidence of hypoxic ischaemic change.
Both twins had decreased muscle mass, temporal scalloping, thin ribs, long fingers and bilateral undescended testes. On further questioning, a history of polyhydramnios with decreased fetal movements in utero was obtained. The physical examination and lack of hypoxic ischaemic change on MRI suggested a neuromuscular disorder. A full metabolic screen revealed no abnormality. Spinal muscular atrophy (SMA) gene mutations for spinal muscular atrophy were not found. Nerve conduction velocity studies on twin 1 were normal.
On day 26, twin 2 deteriorated rapidly with increasing ventilatory requirements. Given the poor prognosis, the parents chose to forego continued intensive care and palliative care was instituted and he died shortly thereafter in his parents' arms. A post-mortem muscle biopsy showed features consistent with centronuclear (e.g. myotubular) myopathy. On light microscopy, the majority of fibres were small, with occasional central nuclei. On electron microscopy, approximately 30% of muscle fibres had centrally located nuclei and mitochondria. In additional fibres, Z-band streaming and loss of sarcomere organisation was readily apparent. Cytogenetics showed a male karyotype with no cytogenetic abnormality. DNA was sent for molecular studies of the MTM1 gene. A direct sequence analysis of the entire coding region of the MTM1 gene identified a hemizygous deletion of the T nucleotide at position 431 in exon 6 (c.431delT [p.Leu144fs]), which results in frameshift at codon 144.
Twin 1 was eventually successfully extubated to continuous positive airway pressure (CPAP) on day 43 of life. A repeat MRI of the brain showed bilateral cephalhematomas, a prominent left cisterna magna but no focal brain abnormality was identified. Several attempts to wean from CPAP were unsuccessful. Extensive discussions were held with his parents because of the poor long-term prognosis. On day 69 of life, a decision was made for palliative care management and he died peacefully in his parents, arms later that day. Zygosity studies of the twins revealed that they were monozygous.
- 1X linked myotubular myopathy is a rare neuromuscular disorder which may present in the newborn as hypoxic ischaemic encephalopathy.
- 2Clinical manifestations like hypotonia and lethargy in newborn must be evaluated diligently and may point towards underlying neuromuscular and metabolic disorder.
- 3Myotubular myopathy may be associated with subdural hygromas and cephalhaematomas.