Hypotonic Infants Research Articles

Is an Algorithm Useful in the Differential Diagnosis of the Hypotonic Infant? Evaluation of 53 Cases

Is an Algorithm Useful in the Differential Diagnosis of the Hypotonic Infant? Evaluation of 53 Cases

Case Scenario: Hypotonia in Infancy

NFANTS with hypotonia of unknown etiology pose a unique challenge as many of the potential diagnoses have major, often conflicting, anesthetic management implications. The differential diagnosis of hypotonia is long and includes possibilities such as Duchenne muscular dystrophy, central core disease, and multiminicore disease. Intravenous anesthetic techniques are recommended because hyperkalemia or malignant hyperthermia is associated with the use of volatile anesthetics. However, the differential diagnosis of infants with hypotonia also includes mitochondrial disorders. In children with mitochondrial disorders, an intravenous anesthetic technique that includes propofol could lead to metabolic decompensation because propofol alters mitochondrial electron transfer. This dilemma is often encountered when hypotonic infants require anesthesia for diagnostic tests such as magnetic resonance imaging and muscle biopsies for definitive diagnosis.

Hipotonía en el período neonatal: 12 años de experiencia

Hypotonia is one of the most frequent signs of neurological pathology in newborn infants. To determine, in a 12-year retrospective study, the relative frequency of neurological pathologies that can be accompanied by hypotonia during the neonatal period and to describe the neurological development after two years' follow-up. We conducted a systematic review of the newborn infants with hypotonia due to an identifiable cause who were admitted to the neonatal unit of the Hospital Sant Joan de Deu between January 1996 and December 2008. Information collected referred to family history, data related with the pregnancy and childbirth, clinical features and complementary tests. RESULTS. A total of 73 hypotonic newborn infants were identified, 21 (28.7%) of whom met eligibility criteria. The majority, 81% (n = 17), were classified as central hypotonias and the remaining 19% (n = 4) were graded as peripheral hypotonias. In the first group, 47% (n = 8) presented chromosomal disorders, 29.4% (n = 5) had metabolic diseases and 23.5% (n = 4) displayed malformations of the central nervous system. The central causes of hypotonia continue to be the most prevalent in the neonatal period and, within these, chromosomal disorders are the most frequent. Peripheral causes are less common and have a more severe prognosis. Advances in molecular genetics have allowed many neuromuscular diseases to be diagnosed both genetically and at the molecular level. The diversity and complexity of the pathologies justifies a multidisciplinary approach being taken to treat these newborn infants.

1034 A Hypotonic Infant with Methylene Tetrahydrofolate Reductase (MTHFR) Deficiency; Homozygous Mutation of C.1015T>G in Mtfhr Gene

BackgroundMethylene tetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder, caused by mutated alleles of the MTHFR gene. Since this enzyme catalyzes the conversion of 5.10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, its...

G.P.73 Abnormal neuromuscular transmission in infants with Prader–Willi syndrome

Abstract Prader–Willi Syndrome (PWS) is a multi-system disorder caused by absent expression of the paternal region of chromosome 15q11–13. Newborns with PWS are severely hypotonic and inactive, with subtle dysmorphic features (almond shaped eyes, small hands and feet and hypogonadism). Ability to suck is reduced and feeding problems are common, however respiratory distress is rare. Characteristically, within weeks, these infants become more responsive and develop more spontaneous movement. The aetiology of the extreme hypotonia is unknown, however both central factors and primary muscle pathology have been proposed. We describe five infants with severe hypotonia, feeding difficulties and varying degrees of respiratory distress. The diagnosis of PWS was initially not clinically apparent therefore they underwent neurophysiological assessment, including stimulated single fibre EMG (SSFEMG) of orbicularis oculi. SSFEMG was considered abnormal if the grand average of the mean consecutive difference (MCD), of the intervals between the stimulus and the potential (the jitter), was greater than 26 μs, or if more than 10% of the individual measurements were greater than 34 μs. All five infants showed significant abnormalities in SSFEMG, suggestive of a neuromuscular transmission disorder. Jitter measurements ranged from 34.6 to 68.7. One infant was initially diagnosed with congenital myasthenic syndrome and responded well to treatment with pyridostigmine. Cytogenetic studies subsequently confirmed the diagnosis of PWS in all five cases. This is the first report of abnormal SSFEMG findings in infants with PWS. We suggest that these infants may have an abnormality in neuromuscular junction transmission contributing to their early hypotonia and inactivity, which improves with maturation. PWS should therefore be considered in the differential diagnosis of hypotonic infants with neuromuscular junction abnormalities diagnosed by SSFEMG.

NICU Network Neurobehavioral Scale Profiles Predict Developmental Outcomes in a Low‐Risk Sample

Latent profile analysis (LPA) has been used previously to classify neurobehavioral responses of infants prenatally exposed to cocaine and other drugs of abuse. The objective of this study was to define NICU Network Neurobehavioral Scale (NNNS) profile response patterns in a cohort of infants with no known cocaine exposure or other risks for neurobehavior deficits, and determine whether these profiles predict neurobehavioral outcomes in these low-risk infants. NNNS exams were performed on 355 low-risk infants at approximately 5 weeks after birth. LPA was used to define discrete profiles based on the standard NNNS summary scales. Associations between the infant profiles and neurobehavioral outcomes at one to three years of age were examined. Twelve of the 13 summary scales were used and three discrete NNNS profiles identified: social/easy going infants (44%), hypotonic infants (24%), and high arousal/difficult infants (32%). Statistically significant associations between NNNS profiles and later neurobehavioral outcomes were found for psychomotor development and externalizing behaviors. Hypotonic infants had both lower psychomotor development and lower externalizing scores compared to the other two profiles. Three distinct profiles of the NNNS summary scores were identifiable using LPA among infants with no known cocaine exposure. These profile patterns were associated with early childhood neurobehavioral outcome, similar to findings reported in a study of infants with substantial cocaine exposure, demonstrating the utility of this profiling technique in both exposed and unexposed populations.

Neuromuscular Diseases Causing Floppy Infant Syndrome

We refer to a floppy infant as an infant with generalized hypotonia presenting at birth or in early life. There is a broad spectrum of underlying conditions, which can either be acquired or of genetic origin, leading to a reduction in muscle tone and floppy infant syndrome. One aim when assessing a hypotonic infant is to localize the underlying cause of the condition to the upper or lower motor unit. The presence of hypotonia in combination with weakness in the limb muscles and reduced reflexes suggests a lesion of the lower motor unit or neuromuscular disease. The lesion can either be in the anterior horn cell, as in spinal muscular atrophy, the peripheral nerve, as in the hereditary neuropathies, the neuromuscular junction or the muscle fibre itself. Studies have suggested that about a third of floppy infants admitted to the neonatal intensive care unit are affected by a neuromuscular disease. In most cases the primary defect is within the muscle fibre resulting in a form of congenital myopathy, congenital muscular dystrophy or a metabolic myopathy. Diseases of the neuromuscular junction presenting as floppy infant syndrome can be acquired or hereditary. Over the recent years a growing number of congenital myasthenic syndromes has been identified, many of which can be treated if adequately diagnosed. With new therapies hovering above the horizon and in order to counsel families properly it becomes increasingly important to make a precise diagnosis and to understand the natural history of neuromuscular diseases causing floppy infant syndrome.

Cranial magnetic resonance imaging findings of nutritional Vitamin B12 deficiency in 15 hypotonic infants

BackgroundNutritional vitamin B12 deficieny is common among infants in the developing and underdeveloped countries. There is limited information concerning neuroimaging findings in infants with vitamin B12 deficiency in the literature. AimsThe aim of this study is to evaluate the cranial magnetic resonance imaging (MRI) changes and clinical characteristics of hypotonic infants due to vitamin B12 deficiency. Materials and methods: A total of 15 infants with neuroradiologic investigations were diagnosed with nutritional B12 vitamin deficiency. Cranial MRI was performed on all infants. ResultsFive infants were female (33%) and the mean age of infants was 12.3 ± 5.5 months. Hypotonia and neurodevelopmental retardation were present in all patients. MRI demonstrated thinning of the corpus callosum in 6 (40%), cortical atrophy in 5 (33.3%), large sylvian fissures in 5 (33.3%), ventricular dilatation in 3 (20%), asymetric large lateral ventricle in 2 (13.3%) and delayed in myelination in 2 (13.3%) patients. Four infants had normal MRI findings. ConclusionBecause of the importance of vitamin B12 in the development of the brain, MRI findings may be detected and useful in infants with vitamin B12 deficiency.

Primary Adenosine Monophosphate (AMP) Deaminase Deficiency in a Hypotonic Infant

The spectrum of the adenosine monophosphate (AMP) deaminase deficiency ranges from asymptomatic carriers to patients who manifest exercise-induced muscle pain, occasionally rhabdomyolysis, and idiopathic hyperCKemia. However, previous to the introduction of molecular techniques, rare cases with congenital weakness and hypotonia have also been reported. We report a 6-month-old girl with the association of congenital muscle weakness and hypotonia, muscle deficiency of adenosine monophosphate deaminase, and the homozygous C to T mutation at nucleotide 34 of the adenosine monophosphate deaminase-1 gene. This observation indicates the possible existence of a primary adenosine monophosphate deaminase deficiency manifested by congenital muscle weakness and hypotonia.

Small nuclear ribonucleoprotein polypeptide N quantitative methylation analysis in infants with central hypotonia

Central hypotonic is one of the most difficult issues in neurology, ruling out neurogenetic syndromic causes is critical, Prader-Willi syndrome (PWS) it is the most frequent genetic syndrome, it is caused by the loss of expression of the paternal allele in a group of imprinted genes within 15q11-q13, and is characterized by severe prenatal and postnatal hypotonia. SNURF-SNRPN gene methylation detects 99% of the cases but fluorescent in situ hybridization (FISH) analysis is necessary to confirm chromosome microdeletions. The advantage of SNRP-quantitative strategy of methylated alleles is that it makes it possible to make the diagnosis and identify deletions and mosaicism in one reaction. In infants clinical diagnosis is difficult. It has been proposed that around 40% of hypotonic patients have PWS but an accurate percentage has not been established. Twenty-four central hypotonic infants were studied by this molecular strategy, showing 41.5% with the disease. This molecular approach also permitted calculation of gene dosage and detection of those cases with microdeletion.

Severe nemaline myopathy associated with consecutive mutations E74D and H75Y on a single ACTA1 allele

Nemaline myopathy is among the most common congenital myopathies. We describe for the first time a novel double de novo mutation in two adjacent codons resulting in two amino acid changes E74D and H75Y in the ACTA1 gene. The hypotonic male infant was the first son of healthy unrelated parents with no family history of neuromuscular disorders. Pregnancy was complicated: decreased fetal movements were noted on the 25th week of gestation, premature labour pains were present from the 29th week onwards and because of breech presentation a Caesarian section was carried out in the 39th week. The patient presented with multiple congenital fractures and joint contractures. He was dependent on ventilatory support until his death at 2 months. Muscle biopsy revealed severely atrophic and rounded muscle fibers with considerable variation in diameter and pronounced disorganization of the myofibers. Electron microscopy indicated a distinct disturbance of the myofibrillar architecture and nemaline rods. In view of previously described cases carrying different single missense mutations of the amino acid residues E74 or H75, we suggest that the particular genotype E74D/H75Y is compatible with the severity of the patient’s phenotype. The possibility of germ cell mosaicism should be taken into account in genetic counseling.

G.P.13.15 Diagnosis and outcome of hypotonia in infancy

Hypotonia in infancy can be the presentation of a wide range of neurological disorders. Despite extensive investigations, many infants remain undiagnosed. We describe our experience of investigation and diagnosis of hypotonic infants with a review of the survival rate at 1 year and identification other co-morbidities. A prospective, ethically approved, study of hypotonic infants referred to our tertiary neuromuscular clinic over a period of two years was carried out. Data was collected at both, at the initial, and 1 yr follow-up appointment noting perinatal history, age and severity of presentation, age and modality of diagnosis, survival at 1 yr and comorbidities.

Benign paroxysmal tonic upgaze of childhood in a hypotonic infant with Beckwith–Wiedemann syndrome

Benign paroxysmal tonic upgaze of childhood in a hypotonic infant with Beckwith–Wiedemann syndrome

Síndrome de Wolf-Hirschhorn: Microdeleción distal del brazo corto del cromosoma 4

ABSTRACT Wolf-Hirschhorn Syndrome: distal microdeletion of chromosome 4 short arm Background: Wolf-Hirschhorn Syndrome is a genetic disease, in which the defect is a partial deletioninvolving the distal part of the short arm of chromosome 4. The clinical manifestations are craniofacialanomalies, delayed psychomotor development and neurological disorders. Objetive: Describe a clinicalcase of Wolf-Hirschhorn Syndrome, with specific description of craniofacial dysmorphological features. Case report: A female hypotonic infant with microcephaly and facial dysmorphism like greek helmet:prominent glabela, ocular hypertelorism, epicanthal folds and marked broad-beaked nose, with pre andpostnatal severe growth deficiency, mental retardation and seizures. Conclusions: The fluorescence insitu hybridization (FISH) karyotype revealed loss of genetic material at chromosome 4 short arm, withdeletion in band 4p15 confirming the diagnosis. A case of probable de novo mutation with deletion of geneWHSC1 and other linked contiguous genes.(

The association of hypotonia and depression in the term and near-term neonate with metabolic acidemia

To determine the association of hypotonia and depression in neonates at or near term with metabolic acidemia at birth (umbilical arterial pH<7.0 and base excess <-12 mM). This case-control study identified 87 infants without chromosomal or congenital abnormalities born at a single university hospital between 7/91 and 10/04 with hypotonia at birth requiring resuscitation and admission to the neonatal intensive care unit that had a cord gas at delivery. Controls were the subsequent delivery with a cord gas matched by gestational age. Cases and controls did not differ in gestational age (38.7+/-1.9, 38.6+/-1.9 weeks) or birth weight (3,066+/-664, 3,171+/-655 g, P=0.20). Cases were more likely to have a cord pH<7.0 [17 (20%) vs. 1 (1.1%), P=0.0001] and cord pH 7.0-7.1 [13 (14.9%) vs. 2 (2.3%), P=0.003]. Among the hypotonic infants, 31 (35.6%) also were depressed at birth with a 5-min Apgar <7. In the depressed subset of hypotonic neonates 14/31 (45%) had a pH<7.0. Of the 12 hypotonic neonates with seizures, 3 (25%) had pH<7.0. Multivariate analysis showed a significant association between neonatal hypotonia and hypoglycemia, umbilical arterial pH, and nucleated red blood cell count. Although metabolic acidemia is significantly associated with hypotonia at the time of birth, the majority of neonates with hypotonia and depression or seizures do not have objective evidence of asphyxia as measured by a cord gas at the time of delivery.

A Hypotonic Infant With Tachycardia and Fever of Unknown Origin

A Hypotonic Infant With Tachycardia and Fever of Unknown Origin

Duplication of distal 20q: clinical, cytogenetic and array CGH Characterization of a new case

Trisomy of the long arm of chromosome 20 is rare. We describe an 18-month-old male who was born at 36 weeks via Caesarian section after an uneventful pregnancy. During the newborn period he was found to have a right-sided cleft lip and cleft palate, hypertelorism, strabismus and mildly over-folded ears with cupping. Cardiovascular examination was consistent with the diagnosis of severe aortic coarctation, which was confirmed by echocardiogram. Additionally, hypothyroidism was diagnosed. Neurological evaluation at 18 months revealed a hypotonic infant with delayed acquisition of motor milestones. Cytogenetic analysis showed additional material on the long arm of chromosome 20, confirmed by fluorescence in situ hybridization (FISH) analysis as being of chromosome 20 origin. Because of the indistinct GTG-banding pattern it was not possible to distinguish between a proximal [dup(20)(q11.2q13.1)] or distal duplication [dup(20)(q13.1q13.3)]. To further define the duplication we used array comparative genomic hybridization (CGH) which demonstrated a 7.8 Mb interstitial duplication in distal 20q. Thus, the proband's karyotype was interpreted as 46,XY,dup(20)(q13.2q13.2). The proband is the first reported case of a pure duplication of this region. This case further highlights the utility of array CGH in characterizing aneusomies and, in particular, for accurate breakpoint designation and quantitation of ambiguous rearrangements.

A schematic approach to hypotonia in infancy

Hypotonia may be the presenting sign for many systemic diseases and diseases of the nervous system. The present paper discusses a rational, simple and accurate diagnostic approach to hypotonia in infancy, illustrated by the case of a five-month-old infant girl recently referred to the IWK Health Centre in Halifax, Nova Scotia. Key points in the history and physical examination are outlined to allow a tailored investigation both for the patient and for other hypotonic infants. A discussion of an important neuromuscular disease, diagnosed in the present patient, concludes the paper.

Cytogenetic and Molecular Diagnoses of Hypotonia in the Newborn

After completing this article, readers should be able to: 1. Describe the important history and examination considerations for the evaluation of a hypotonic infant. 2. Describe the spectrum of testing that should be considered for a newborn who has hypotonia. 3. Name the most frequent chromosomal abnormality associated with hypotonia in the nursery. 4. Describe the limitations of fluorescence in situ hybridization technology in the laboratory diagnosis of Prader-Willi syndrome. 5. Explain the differences in inheritance and genetic counseling concerns between myotonic dystrophy and spinal muscular atrophy. The availability of molecular and cytogenetic techniques has improved our ability to make genetic diagnoses during the newborn period. Clues from both prenatal and familial histories in combination with findings on the infant’s physical examination are vital for appropriate test selection. However, even with such clues, the examiner may be left with a broad differential diagnosis to consider and require input from many pediatric subspecialists. Diagnosing hypotonia in the newborn period is an important example of how genetic testing can aid significantly in timely diagnosis for a critically ill newborn and allow for anticipation of medical interventions by the multidisciplinary team caring for the infant. When an infant’s postural tone (muscle tone maintained against gravity) is decreased compared with normal, the infant often is described as hypotonic. Phasic hypotonia, a decrease in rapid contraction in response to stretch, also may be present, as evidenced by examination of peripheral reflexes. Both findings are important pieces of information for the examiner because the presence of hypotonia elicits a very broad differential diagnosis for both pediatric neurologists and geneticists. The challenge is to find the origin of the hypotonia. What clues can localize it to the brain, spinal cord, peripheral nerve, or muscle? Based on this localization, what appropriate testing is available? A thorough prenatal history may describe decreased fetal movement, …

The myopathology of floppy and hypotonic infants in Singapore

This study attempts to determine the type and relative frequency of muscle diseases contributing to floppy and hypotonic infants in Singapore. Eighty consecutive muscle biopsies in the Department of Pathology, National University of Singapore, in the period 1978-2000, in which a clinical diagnosis of floppy or hypotonic infant was made, were reviewed. The commonest cause of severe hypotonia in infancy was spinal muscular atrophy, which accounted for 33% of cases followed by congenital muscular dystrophy (13%). Eight cases (10%) of infantile type II glycogenosis (Pompe's disease) were encountered. There were seven cases of congenital myopathy, of which four were centronuclear myopathy, and one each of central core myopathy, nemaline myopathy and congenital fibre type disproportion. One case of centronuclear myopathy was associated with type I fibre smallness. Type II atrophy, which is generally considered a non-specific change, was encountered in five cases. Of interest is the relatively large number of muscle biopsies (29%) in which no significant pathological features were encountered at the light microscopic, histochemical as well as ultra-structural level. The study has revealed a great variety of pathology affecting the muscle of children presenting as floppy infants or with hypotonia. The muscle diseases included spinal muscular atrophy, congenital muscular dystrophies, congenital myopathies and metabolic myopathies. However, 23 (29%) cases showed no significant pathology. For this group of floppy and hypotonic infants further studies are needed.