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.     

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.     

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.     

Recessive osteopetrosis. Identification of a form of medium severity]

BACKGROUND. Several distinct forms of osteopetrosis have been identified. Some of the autosomally recessive inherited forms are benign, much like the autosomal dominant form. Others are more malignant. PATIENTS. The clinical data, skeletal radiographs, histological features and histories of 32 children with osteopetrosis were analyzed retrospectively. RESULTS. The 32 patients, belonging to 20 sibships were divided into two groups. The first group included 24 patients, aged 1 day-11 months (mean 4.5 months), suffering from hepatosplenomegaly, anemia, thrombocytopenia and optic atrophy in early infancy. They also had a generalized increase in bone density, abnormal bone remodeling, rachitic lesions and a "bone-within-bone" appearance. Biopsies showed severe bone resorption and myelofibrosis. 19 of the 20 patients whose outcomes were known died during the first year of life. The second group included 8 patients, aged 40 days-3 years (mean: 11 months). Hepatosplenomegaly appeared later, anemia was less severe and thrombocytopenia occurred in only 1 patient. However, all 8 patients suffered from optic atrophy and 3 were deaf. Radiographs showed bone growth without rachitic lesions. Biopsies from 2 patients showed bone resorption, but no myelofibrosis. The outcome was less severe: 6 patients, now aged 8 months to 8 years, have survived, 3 of them for over 5 years. Genetic investigation showed patterns compatible with autosomal recessive inheritance in both groups, with similar sets of features within each sibship. CONCLUSION: This study reveals a new type of recessively inherited osteopetrosis. It can be classified as an intermediate form, distinct from both the malignant and the benign forms, and also distinct from osteopetrosis with carbonic anhydrase II deficiency.     

Hearing loss in facioscapulohumeral dystrophy

Bilateral sloping high frequency hearing loss of 20–90 dB was found in six out of ten patients with infantile or adolescent onset FSHD. In all cases the basic defect could be traced to the cochlea. The outer hair cells of the basal turn are predominantly affected. In 20 patients with various other forms of muscular dystrophy or neuromuscular disorders with an FSH distribution, no sensorineural hearing loss was found. Myopathology of FSHD patients extended from mild to severe, often showing inflammatory infiltrates and type I fibre atrophy, without unequivocal differences between the two groups with and without hearing loss. It is concluded that cochlear dysfunction is a specific and frequenct phenomenon of early onset FSHD.Abbreviations FSH facioscapulohumeral - FSHD facioscapulohumeral dystrophy - MD muscular dystrophy - SISI short increment sensitivity index     

Distinguishing Cardiac Features of a Novel Form of Congenital Muscular Dystrophy (Salih CMD)

The cardiac features of a novel form of congenital muscular dystrophy (Salih CMD) are described in two adolescent siblings. The patients presented with severe hypotonia at birth, associated with delayed development. They could walk independently and managed to maintain walking after 13 years of age. Their muscle immunohistochemistry differed from that seen in Duchenne and Becher muscular dystrophy (DMD and BMD), severe childhood autosomal recessive muscular dystrophy (SCARMD) due to sarcoglycan deficiency (sarcoglycanopathies), and lamininα2 (merosin)-deficient CMD. However, both patients had associated cardiomyopathy. Electrocardiography (ECG) in Salih CMD was characterized by delayed atrioventricular (AV) conduction, left anterior fascicular block (left axis deviation), and left atrial enlargement without evidence of atrial dysarrhythmia. Echocardiography showed features of severe left ventricular dysfunction with estimated left ventricle ejection fraction (LVEF) of 25% at 16 years-of-age in the older patient. A year later, multigated aquisition MUGA scan showed LVEF of 21% and dilatation of the right ventricle. Echocardiography and MUGA scan were normal in the younger patient at 15 years-of-age. ECG, echocardiography, and MUGA scan are effective techniques for diagnosing and monitoring the cardiomyopathy in Salih CMD. They can also distinguish it from features seen in the other common forms of MD, including DMD, BMD, and sarcoglycanopathies.     

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.     

Motor nerve conduction velocity in spinal muscular atrophy of childhood.

The ulnar and posterior tibial conduction velocities were measured in 29 children with spinal muscular atrophy, 14 of whom had the servere form of the disease. The ulnar nerve velocity was slow in 12 of the 14 severely affected infants, but normal or fast in 11 of 14 children less severely affected. The corresponding results for the posterior tibial nerve were slow velocities in 11 of 12 infants in the severe group and normal or fast in all 11 infants less severely affected. The difficulty in distinguishing infantile spinal muscular atrophy from peripheral neuropathy is emphasized.     

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.     

Correlation of SMN2, NAIP,p44, H4F5 and Occludin genes copy number with spinal muscular atrophy phenotype in Tunisian patients

ObjectivesSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder which is characterized by a high clinical variability with severe, intermediate, mild and adult forms. These forms are caused, in 95% of cases, by a homozygous deletion of exon 7 of SMN1 gene. Our purpose was the determination of a possible genotype–phenotype correlation between the copy number of SMN2, NAIP, p44, H4F5 and occludin genes localized in the same SMN1 region (5q13) and the severity of the disease in SMA Tunisian patients.Patients and methodsTwenty six patients affected by SMA were enrolled in our study. MLPA and QMPSF were used to measure copy numbers of these genes.ResultsWe found that 31.3% of type I patients carried one copy of SMN2, while all patients of other forms had at least 2 copies. NAIP was absent in 87.5% of type I patients. Furthermore, all SMA type I patients had one copy of H4F5. No correlation was found for p44 and occludin genes.ConclusionThere is a close relationship between SMN2, NAIP and H4F5 gene copy number and SMA disease severity, which is compatible with the previous reports.     

Suppurated pneumococcal meningitis in infants and children: complications and prognostic factors

This paper investigates 21 patients (16 infants and 5 children) with Pneumococcal meningitis, 15 of which presented with a severe form. Intracranial pressure (IP) monitoring was performed in 7 patients who all had severe (4) or mild (3) intracranial hypertension (IH). Twelve children had a favourable outcome, 7 had sequelae (3 severe) and 2 died from coning, one before monitoring, the second after exhibiting the highest IP and the lowest cerebral perfusion pressure of the series. The 3 children with severe sequelae had a severe form (2) or a mild but prolonged form (1) of IH. The 4 patients who recovered with moderate sequelae presented severe (1), mild IH (1) or were not monitored (2). There were 14 cases with neurological complications. In 8 patients, this seemed to be related to cerebral oedema and IH; coning caused the death of 2 of them; the 6 others exhibited lesions of cerebral oedema on CT-scan, isolated or associated with cerebral infarction or subdural effusion. In the 6 others patients, IP monitoring was not performed; there was no evidence of cerebral oedema on CT-scan; 2 exhibited cerebral infarction and 3 a moderate ventricular dilatation; 2 had hemodynamic problems from acute pneumococcemia in one case and neurovegetative disturbances associated with cerebral infarction in the second. Pneumococcus meningitis remains a severe disease. The prognosis of severe forms can be improved by IP monitoring since IH seems to be the most frequent mechanism of complication.     

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.     

Prenatal onset spinal muscular atrophy.

Five patients with severe spinal muscular atrophy (SMA) type I, all of whom presented with reduced fetal movements in utero, severe weakness at birth, and short survival time were assessed to attempt to determine whether their phenotype could be explained by their genotype. The diagnosis was confirmed by clinical, electrophysiological and histopathological features. Polymerase chain reaction assays were used to define the molecular diagnosis. A gene-dosage assay was used to assess the quantity of centromeric survival motor neuron gene (SMNc) present. In all cases the telomeric survival motor neuron gene (SMNt) was absent. The SMNc gene was present but in reduced copy number compared with a control group of children with less severe type I SMA, so may be important in determining severity. In the differential diagnosis of reduced fetal movements, SMA should be considered. The clinical classification may in future be clarified by molecular genetic findings.     

心电图在重度肺动脉瓣狭窄诊治中的价值

目的 探讨心电图在重度肺动脉瓣狭窄（PS）诊治中的应用价值。方法 结合心脏超声和心导管检查结果，对34例单纯性重度PS患儿（男21例，女13例；平均年龄3．5岁）经皮球囊肺动脉瓣成形术（PBPV）前后心电图进行分析；并与34例轻中度患儿心电图进行比较。结果 单纯重度PS的心电图电轴极度右偏、P波及VIR波振幅增高，与轻中度PS比较存在显著差异（P〈0．05）；V1T波振幅与重度PS的右心室压力、跨肺动脉瓣压力阶差呈直线正相关（r=0．81，0．82 Pα〈0．05）；PBPV不同疗效组间心电图比较无显著性差异（P〉0，05）；PBPV术后近期心电图随访显示，其在心电轴、V1R波的电压、V1T波异常方面均有显著好转（Pα〈0．05）。结论 心电图对PS严重程度具有一定的诊断价值；根据V1R波振幅可估测右心室压力和跨肺动脉瓣的压力阶差；心电图无法预测PBPV术的疗效，但对PBPV术后的随访有重要辅助作用。     

Fulminant form of acute disseminated encephalomyelitis in a child treated with mild hypothermia

We describe the case of a 3‐year‐old boy diagnosed with the fulminant form of acute disseminated encephalomyelitis (ADEM). He developed general fatigue, fever, drowsiness and difficulty in walking. He had extensive multiple high‐intensity lesions in the white matter of the cerebrum and cerebellum, which are typical findings of ADEM. He became comatose and developed decerebrate rigidity with severe brain edema despite high‐dose methylprednisolone therapy, and then was subjected to mild hypothermia therapy, and given i.v. immunoglobulin. The patient recovered remarkably with the sequela of only mild action tremor. The patient was considered to have acute hemorrhagic leukoencephalitis (AHLE), an extremely severe form of ADEM, in terms of the rapidly deteriorating clinical course and neuroimaging features. It was speculated that AHLE and ADEM might be a continuous disease spectrum. It is considered that the severe brain edema associated with ADEM or AHLE is a suitable indication for mild hypothermia therapy.     

Clinical hints to diagnosis of attenuated forms of Mucopolysaccharidoses

The mucopolysaccharidoses (MPS) are clinically similar but also heterogeneous in terms of major or minor involvement of different organs/systems, burden of disease, and rate of progression. The attenuated forms of MPS, due to their less severe presentations, are more difficult to diagnose and often receive a significantly delayed diagnosis. On the other hand, the diagnosis is very important since the attenuated forms may benefit from earlier treatments. The aim of this paper is to describe the natural history and the clinical signs useful to arise a suspicion of an attenuated form of MPS. MPS patients usually show a cluster of signs and symptoms, one of which may be the trigger for an evaluation by a specialist. Individuals with attenuated MPS are mostly cognitively normal, and dysmorphisms of the facies may be mild or absent. The most frequently involved organs/systems are the osteoarticular system, heart, and eyes. These patients may also have hepatosplenomegaly, hearing loss, and respiratory problems. When they are referred to a specialist (rheumatologist, cardiologist, ophthalmologist, surgeon, orthopedist, etc.) for their main complaint, the other signs and symptoms are likely to be missed in the medical history. To avoid missing data and to save time, we propose a semistructured medical history form to be filled in by the patients or their caregivers while waiting for evaluation by a specialist.     

Congenital hyperextension of the knees in twins

Bilateral congenital hyperextension of the knees occurring in dizygotic twins is reported. Twin A had the mild form of the disease, genu recurvatum, while twin B had a more severe form of the disease, congenital subluxation. Hyperextension of the knee may occur as a sporadic abnormality, in conjunction with multiple dislocations or as a feature of a syndrome. Early detection and diagnosis are important, especially in the more severe forms of the condition, subluxation and dislocation, which require aggressive immediate intervention to prevent long-term sequelae. Conservative treatment consisting of manipulations and immobilization usually will correct the mild forms of the condition if instituted soon after birth. Prognosis is less favorable with delayed treatment, in the presence of other congenital anomalies, and with genetic syndromes.     

Early growth is not increased in untreated moderately severe 21-hydroxylase deficiency

The pretreatment growth of 1 British and 14 Swedish children with late (2-7 years) diagnosis of 21-hydroxylase deficiency (210HD) was studied. The latter group included all patients diagnosed in Sweden after 1986. Twelve had mutations of the 21-hydroxylase gene that are generally associated with moderately severe (“simple virilizing”) forms of 210HD, one had a severe (“salt-losing”) and one a mild (“non-classical”) form. The British girl was followed from 4 months of age. She had grossly elevated levels of 17a-hydroxyprogesterone, androstenedione and testosterone in blood, but her parents refused treatment until she was 4 years of age. None of the 15 children showed any significant increase in growth or progress of virilization until after 18 months of age. These observations indicate that growth during the first 1.5 years is not very sensitive to androgens. Thus glucocorticoid replacement during the first year of life should be kept to a minimum to avoid over-treatment.Congenital adrenal hyperplasia, CYP21, genotype, growth, infancy EM Ritzen, Pediatric Endocrinology Unit, Karolinska Hospital, S-171 76 Stockholm, Sweden     

Infantile tremor syndrome

Nine patients of infantile tremor syndrome from Afghanistan are reported. There were eight males and one female. Their ages ranged between 11 and 24 months (mean 17.4 months). All except two patients were seen during the months of March and April. Seven children had associated mild to moderate malnutrition, while all had mild to moderate anemia. Exclusively breast feeding was observed in only 3 infants. Retardation of physical and mental development started around 7 to 9 months of age in all. Four infants had suffered from known viral infections (two had measles, one each had chicken pox and infectious hepatitis) within 2–3 weeks of the onset of tremors. Patients were administered multivitamins, iron, high protein diet and phenobarbitone with variable response. It is concluded that infantile tremor syndrome does exist outside India and this condition should not be designated as “Indian childhood tremor syndrome” as suggested by some authors.     

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.