Infantile spinal muscular atrophy with respiratory distress type I (SMARD 1): An atypical phenotype and review of the literature

Spinal muscular atrophy with respiratory distress (SMARD 1) is a very rare autosomal recessive motor neuron disorder that affects infants and is characterized by diaphragmatic palsy, symmetrical distal muscular weakness, muscle atrophy, peripheral sensory neuropathy and autonomic nerve dysfunction. SMARD 1 is inherited as an autosomal recessive trait and the mutations have been identified in the gene encoding immunoglobulin μ-binding protein 2 (IGHMBP2), located on chromosome 11q13. It is considered a fatal form of infantile motoneuron disease and most of the patients dies within the first 13 months of life. We present a female child with genetically confirmed SMARD 1 displaying a mild phenotype and no severe signs of respiratory involvement, typically found in this form, up to 38 months despite a diaphragmatic palsy diagnosed at 6 months of age. Therefore, our clinical observation suggests that respiratory failure is not secondary, in any case, to the diaphragmatic palsy but other pathogenetic mechanisms might be involved.     

Early diaphragmatic paralysis. In infants with genetic disorders

Three infants with recently diagnosed genetic diseases presented with respiratory failure and required assisted ventilation. One infant had spinal muscular atrophy (Werdnig-Hoffmann disease), and two had acid maltase deficiency. The cause of the respiratory failure in all was diaphragmatic paralysis, and they became ventilator dependent. Early diaphragmatic paralysis must be considered as a manifestation of genetic neuromuscular disorders.     

Diaphragmatic paralysis due to spinal muscular atrophy. An unrecognised cause of respiratory failure in infancy?

An unusual form of spinal muscular atrophy presenting with respiratory failure was observed in four infants from two families. In one, whose death was attributed to pneumonia, the diagnosis was inferred retrospectively after two siblings died from an identical illness and were shown to have diaphragmatic paralysis and the typical electrophysiological and histological features of spinal muscular atrophy. Other signs of skeletal muscular weakness were absent or inconspicuous. The fourth, unrelated infant presented in an identical way but has survived for over a year on a ventilator. Two months after the onset of respiratory paralysis, more extensive skeletal muscular weakness was seen. Other infants, dying of unexplained respiratory illness, may have this disorder and some may be included in the miscellany of disorders that constitute the sudden infant death syndrome.     

Inherited motor neuron disease in domestic cats: a model of spinal muscular atrophy

Juvenile-onset spinal muscular atrophy was observed in an extended family of purebred domestic cats as a fully penetrant, simple autosomal recessive trait. Affected kittens exhibited tremor, proximal muscle weakness, and muscle atrophy beginning at ~4 mo of age. Apparent loss of function was rapid initially but progressed slowly after 7-8 mo of age, and variably disabled cats lived for at least 8 y. Electromyography and microscopic examination of muscle and nerve biopsies were consistent with denervation atrophy as a result of a central lesion. There was astrogliosis and dramatic loss of motor neurons in ventral but not dorsal horn gray matter of spinal cord and loss of axons in ventral horn nerve roots. These phenotypic findings were similar to mild forms (type III) of spinal muscular atrophy in humans caused by survival of motor neuron mutations, but molecular analysis excluded feline survival of motor neuron as the disease gene in this family. A breeding colony has been established for further investigation of this naturally occurring large-animal model of inherited motor neuron disease.     

Hand and ECG tremor in spinal muscular atrophy.

The presence of hand and electrocardiogram (ECG) tremor was studied in 31 children with severe, intermediate, or mild form of spinal muscular atrophy. Clinical tremor of the hands was seen in 16 (59%) of 27 patients, all with benign forms of the disease. Nineteen patients had ECG tremors, of whom 17 had the mild or intermediate form. With the exception of one, all patients in the mild or intermediate group had hand or ECG tremor. Hand and ECG tremor are valuable in the diagnosis of the benign forms of spinal muscular atrophy; they are of no value in diagnosis of the severe infantile type.     

Spinal muscular atrophy in childhood: Two clues to clinical diagnosis

A coarse tremor was noted in 13 children suffering from the childhood form of spinal muscular atrophy. Tremor has not been seen in any other condition producing proximal muscle weakness in childhood, and its presence should therefore suggest the diagnosis of spinal muscular atrophy.In addition, the feet of patients with spinal muscular atrophy tended to evert, whereas in Duchenne muscular dystrophy there was either no deformity or a tendency to toe walking.     

Severe phenotypes of SMARD1 associated with novel mutations of the IGHMBP2 gene and nuclear degeneration of muscle and Schwann cells

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a very rare autosomal recessive form of spinal muscular atrophy manifested in low birth weight, diaphragmatic palsy and distal muscular atrophy. Caused by a mutation in the IGHMBP2 gene, the disease is addressed here by reference to five Polish patients in which SMARD1 has been confirmed genetically. All presented a severe form of the disease and had evident symptoms during the second month of life; with four displaying weak cries, feeding difficulties and hypotonia from birth. Two were afflicted by severe dysfunction of the autonomic nervous system. Ultrastructural analysis of a muscle biopsy revealed progressive degeneration within the nuclei of the muscle cells and Schwann cells. Neuromuscular junctions were also defective. It proved possible to identify in our patients 6 novel IGHMBP2 mutations: three missense (c.595G>C, c.1682T>C and c.1794C>A), two nonsense (c.94C>T and c.1336C>T) and one in-frame deletion (c.1615_1623del). One nonsense mutation (c.429C>T) that had been described previously was also identified. Observation of our patients makes it clear that clinical picture is still the most important factor suggesting diagnosis of SMARD1, though further investigations concerning some of the symptoms are required. As the IGHMBP2 gene is characterized by significant heterogeneity, genetic counseling of affected families is rendered more complex. IGHMBP2 protein deficiency can lead to the degeneration of nuclei, in both muscle and Schwann cells.     

Inherited neuromuscular disorders: pathway to diagnosis

Muscle weakness in childhood can be caused by a lesion at any point extending from the motor cortex, brainstem and spinal cord to the anterior horn cell, peripheral nerve, neuromuscular junction and muscle. A comprehensive history and physical examination is essential to aid classification of the neuromuscular disorder and direct gene testing. The more common disorders such as spinal muscular atrophy, Duchenne muscular dystrophy, myotonic dystrophy and facioscapulohumeral dystrophy may be diagnosed on direct gene testing based on the history and clinical examination. The congenital myopathies are classified based on structural abnormalities on muscle biopsy, while protein abnormalities on immunohistochemistry and immunoblotting aid classification of the muscular dystrophies. In this review, we provide an approach to diagnosis of a child with weakness, with a focus on the inherited neuromuscular disorders, and the features on history, examination and investigation that help to distinguish between them.     

Chronic generalized spinal muscular atrophy of infancy and childhood: Arrested Werdnig-Hoffmann disease

Recent studies have shown that the acute fatal form of infantile spinal muscular atrophy (acute Werdnig-Hoffmann disease or spinal muscular atrophy Type I) is a distinct genetic and clinical entity. This has prompted clinical re-examination of the disease known as `arrested Werdnig-Hoffmann disease'' which hitherto was thought to be a spectrum variant of the acute fatal form. A total of 18 such patients with the chronic generalized form of spinal muscular atrophy has been known to The Hospital for Sick Children over the past 10 years. Patients with this characteristic clinical syndrome comprise approximately one-fifth of children with chronic spinal muscular atrophy. Clinically, no patient was even able to crawl normally or progress further with motor milestones. Median age of clinical onset is 6 months of age, and life expectancy ranges from 2 years to the third decade. Inevitable spinal and joint deformities occur by the second decade of life. Management should be based on vigorous antibiotic therapy, orthopaedic and neurological surveillance, and a carefully planned educational programme aimed at realistic employment in late adolescence.     

Spinal muscular atrophy: some easy clues to diagnosis

Seven cases of benign form of spinal muscular atrophy were studied to evaluate the importance of detecting hand tremors, muscle fasciculation, evertion of foot and ECG tremors to distinguish these cases from muscular dystrophy. Taken in combination, diagnosis of all the seven cases was possible without the need for application of more sophisticated and invasive investigations, e.g., EMG, nerve conduction study, CPK levels and muscle biopsy.     

儿童脊肌萎缩症23例临床特点及遗传学分析

目的 探讨脊肌萎缩症的临床特点和遗传方式。方法 对23例脊肌萎缩症患儿的临床资料进行总结,并用Weiber先证法分析其发病的遗传规律。结果 临床特点为出生后双下肢呈对称性弛缓性瘫痪且进行性加重,四肢近端无力,肌张力、肌力低下;肌电图主要表现为神经原性损害。隐性遗传分离分析表明,12个家系23例患儿发病方式符合常染色体隐性遗传。结论 脊肌萎缩症的临床发病早且病死率高,在遗传咨询中注意作相关产前基因检查,可避免该类患儿的出生。     

Motor nerve conduction studies on children with spinal muscular atrophy

Median and posterior tibial motor nerve conduction studies were performed on 10 children with spinal muscular atrophy (SMA). Three patients with SMA type I, in whom rapid deterioration occurred, showed reduced motor nerve conduction velocity and a remarkably low M-wave amplitude in both nerves. In type II and III patients, the motor nerve conduction velocity was normal in the median nerve, although the M-wave amplitude was small in the tibial nerve. In four patients, a reduction of the M-wave amplitude was observed as clinical symptoms advanced. These findings may suggest that motor conduction studies in spinal muscular atrophy provide complementary information for understanding the pathogenesis and are also useful to clarify the heterogeneity of this disease.     

Spinal muscular atrophy: MR evaluation

The neurogenic myopathy of spinal muscular atrophy (SMA) is degeneration of anterior horn cells of the spinal cord and associated muscle weakness. In three patients with the severe type, according to Dubowitz's classification, magnetic resonance imaging (MRI) of the lower extremity showed severe atrophy of the entire muscle bundles of the thigh and the calf. Nine intermediate type patients had ragged atrophy of muscle bundles of the thigh and the calf with selective preservation of adductor longus muscle. Five patients with the mild type had fatty infiltration of muscle bundles and increased intermuscular fat planes. MRI was insufficient for the evaluation of cervical cord abnormalities. MRI of the lower extremity was a reliable complementary modality for the diagnosis and follow-up of SMA patients.     

Spinal muscular atrophy type 1: Is long‐term mechanical ventilation ethical?

We present a baby with spinal muscular atrophy type 1, an inherited disorder causing progressive weakness, leading to complete paralysis of respiratory, facial and limb muscles. Without intervention, death occurs in infancy due to respiratory failure. Mechanical ventilatory support can prolong life, but the child's quality of life is highly debatable. We discuss the appropriateness of initiating and continuing intensive care for this child and others in a similar position.     

Diagnostic trap and difficulties of genetic counseling in a family with neuromuscular disease carriers]

BACKGROUND: Recent advances in the field of molecular genetics have provided useful tools for the diagnosis of neuromuscular disorders. Genetic counselling for many of these conditions may, however, be fraught with difficulties. CASE REPORT: The patient, two paternal uncles and a paternal aunt presented with clinical and electromyographic evidence of type III spinal muscular atrophy despite an autosomal dominant-like pedigree. The diagnosis was confirmed by genetic testing for the SMN deletion. As the proband's mother was pregnant at the time of presentation of the affected child, a prenatal diagnostic test was performed. The deletion was not found in the DNA extracted from the trophoblast and the pregnancy proceeded to full term, and a normal child. At the same time, a first cousin of the proband was found to have a clinically similar condition. He had not the SMN deletion. He presented with electrophysiological and pathological features of limb-girdle muscular dystrophy. Genetic testing revealed a homozygote del T521 mutation of the gama-sarcoglycan gene. CONCLUSION: To provide accurate genetic counselling, it is essential to get precise data on family background and diagnostic confirmation for each affected relative to avoid missing the possibility, albeit rare, of several neuromuscular disorders within a family.     

Hypercalcaemia in infancy; a presenting feature of spinal muscular atrophy

A 10 month old girl presented with a history of constipation from early life. She was found to be hypercalcaemic with hypercalciuria and nephrocalcinosis. Her mild motor delay and hypotonia were thought to be linked to chronic hypercalcaemia, but when these features failed to improve despite normocalcaemia on a low calcium diet the possibility of neuromuscular disease was explored in more detail. She was subsequently found to have spinal muscular atrophy type 2. We suspect that the hypercalcaemia with hypercalciuria observed in this case reflects altered bone turnover secondary to reduced muscular activity.     

Hypercalcaemia in infancy; a presenting feature of spinal muscular atrophy.

A 10 month old girl presented with a history of constipation from early life. She was found to be hypercalcaemic with hypercalciuria and nephrocalcinosis. Her mild motor delay and hypotonia were thought to be linked to chronic hypercalcaemia, but when these features failed to improve despite normocalcaemia on a low calcium diet the possibility of neuromuscular disease was explored in more detail. She was subsequently found to have spinal muscular atrophy type 2. We suspect that the hypercalcaemia with hypercalciuria observed in this case reflects altered bone turnover secondary to reduced muscular activity.     

Infantile spinal muscular atrophy

Summary Seven cases of infantile spinal muscular atrophy are reported. In one child, mental retardation was associated with hypotonia. Similarity between Werdnig-Hoffmann’s disease and Oppenheim’s amyotonia congenita is stressed. The literature is briefly reviewed and the importance of muscle biopsy stressed. From The Department of Pediatrics, Govt. Medical College, Rohtak and Medical College, Patiala.     

The role of palliative care in advanced muscular dystrophy and spinal muscular atrophy

OBJECTIVE: This study examines the potential role for palliative care services in the care of individuals with muscular dystrophy and spinal muscular atrophy, and the support of their families. METHODOLOGY: Semistructured interviews were conducted in South Australia with nine bereaved and four current family members of individuals with muscular dystrophy or spinal muscular atrophy. Issues explored during interview included: (i) the family perceptions of the difficulties in caring; (ii) the psychological and physical resources which were available to assist them; and (iii) family recall of the management of the terminal phase of the illness. RESULTS: Significant issues identified included: (i) a lack of coordination of care and access to skilled, competent carers; (ii) a lack of support for siblings; (iii) inadequate bereavement care; and (iv) limited discussion of options of ventilatory support and advance directives. CONCLUSIONS: The terminal care for individuals with muscular dystrophy and spinal muscular atrophy and their families requires improvement. Although many individuals with these conditions will die following an acute event, palliative care services may be appropriate for those who require a period of terminal care at home.