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Seminars in Fetal & Neonatal Medicine 16 (2011) 99e108

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Seminars in Fetal & Neonatal Medicine

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Genetic evaluation of the oppy infant

A.N. Prasad a, b, d, *, C. Prasad a, c, d

Department of Pediatrics, University of Western Ontario, London, Ontario, Canada Division of Clinical Neurosciences, University of Western Ontario, London, Ontario, Canada c Genetics Program of South Western Ontario, University of Western Ontario, London, Ontario, Canada d Child Health Research Institute, University of Western Ontario, and London Health Sciences Centre, London, Ontario, Canada

s u m m a r y
Keywords: Array comparative genomic hybridization DNA Genetic Hypotonia Infant Metabolic Neonate

Hypotonia in infants in the rst year of life is a common diagnostic and management challenge for pediatricians and neonatologists. Several published clinical studies have shown that a substantial proportion of cases are accounted for by genetic disorders. Rapid advances in biotechnology, bioinformatics, and molecular genetic testing have made it possible to offer specic genetic diagnoses in a timely manner. The value of clinical examination in the localization of hypotonia within the nervous system as the rst step towards a diagnosis cannot be overemphasized. Due importance should be given to specic features on examination and in the selection of appropriate laboratory tests to minimize laboratory costs. Inborn errors of metabolism, although infrequently encountered, are of importance. Based on clinical evidence from published studies, an algorithm is suggested that would incorporate the clinical features and testing modalities in providing a high diagnostic yield for the clinician. 2010 Elsevier Ltd. All rights reserved.

1. Introduction The hypotonic newborn/infant has been given the colloquial designation of the oppy infant. Since the classic monograph on the oppy infant in 1980,1 the list of differential diagnoses has grown substantially longer.2 At times, establishing a specic diagnosis in individual cases can be extremely challenging. Unprecedented advances in genetic technology in the last two decades (molecular and cytogenetics) carry an ever-increasing impact on our abilities to provide a specic diagnosis at a molecular level for genetic disorders. Presently, the practising clinician is under constant pressure to keep up with an expanding list of syndromic diagnoses and the continually evolving modalities of diagnostic testing. Overall, the diagnostic process has been expedited by newer technologies for rapid detection of genomic deletions and duplications [array comparative genomic hybridization (CGH)], and advances in gene sequencing methods.3,4 There is increasing reliance on using bioinformatics as a means of accessing the current status of gene mutations/copy number variants/polymorphisms and their pathological signicance.

The other major contribution to diagnosis has been achieved through the use of increasingly high resolution imaging technologies [cranial magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS)] that not only offer a high degree of resolution in visualizing the brain, but also provide a non-invasive assessment of neurochemical integrity and function. Clinical evidence from several studies support the early use of imaging in improving diagnostic yield.5e7 Finally, it is imperative to consider inherited metabolic disorders or inborn errors of metabolism as an important category in any discussion on genetic disorders that can present with hypotonia in the neonatal period and infancy, as conditions such as Pompe disease can respond to early enzyme replacement therapy. To effectively apply the advances in laboratory diagnosis and imaging, multidisciplinary evaluation by a geneticist, a pediatric neurologist, as well as consultation with a specialist in metabolic disorders, and a pediatric neuroradiologist has become essential. 2. The hypotonic infant; neurological basis and assessment of muscle tone In the majority of infants, hypotonia is often noticed at or soon after birth. The assessment of muscle tone is very much subjective and dependent on a number of variables; chief among them is the experience of the examiner, and the willingness to perform serial and careful assessments. We have found that experienced

* Corresponding author. Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada. Tel.: 1 1519 6858500x57455; fax: 1 15196858350. E-mail address: narayan.prasad@lhsc.on.ca (A.N. Prasad). 1744-165X/$ e see front matter 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2010.11.002


A.N. Prasad, C. Prasad / Seminars in Fetal & Neonatal Medicine 16 (2011) 99e108

neonatal nurses can provide reliably accurate assessments of an infants muscle tone while providing nursing care. The clinical distinction between upper motor neuron and lower motor neuron lesions provides a rational basis for investigation. The examination helps in the precise localization of lesion in the pathway for motor control (central vs peripheral hypotonia) (Fig. 1). Most hypotonic infants demonstrate a characteristic posture of full abduction and external rotation of the legs as well as a accid extension of the arms (Fig. 2A). When traction is delivered to the arms, there is a prominent head lag (Fig. 2B). At least three other maneuvers are employed by neurologists in addition to the pull-to-sit maneuver described: the scarf sign, shoulder (vertical) and ventral (horizontal) suspension. The reader is referred to an excellent description of these evaluation techniques in recent reviews.8,9 With experience, the examiner will gain a sense of the normal range and variation of muscle tone, as well as deviations from the norm in the tone and posture of the newborn or infant. A further challenge arises in neonatal intensive care units during the assessment of the sick preterm infant. In these situations, no denitive conclusions can be drawn from the early examination. Repeated examinations conducted at suitable intervals may be more informative. Investigations may well have to be deferred, until assessments of muscle tone can be more reliably made. The gestational age, the state of alertness of the infant at the time of

examination, and exposure to central nervous system (CNS) depressant medication can all inuence the nal impression of muscle tone. In early infancy, contrary to the expected increase in muscle tone, the response to an upper motor neuron lesion in the early stages is accidity and loss of muscle tone.9 This pattern of hypotonia involves the axial muscles to a greater extent than limb musculature, and is usually associated with preserved or hyperactive reexes. Infants with severe CNS abnormalities develop signs of impairment in level of consciousness, feeding difculties, seizures, apneas, and hiccups. The examination will conrm abnormal posturing, additional abnormalities of ocular movements and of brain stem reexes in addition to hypotonia. The relative preservation of muscle power with hypotonia, and hypereexia favors a central origin to the hypotonia. The relative preservation of alertness, profound weakness, absence of deep tendon reexes suggest a disorder of the lower motor neuron (LMN),8,10 whereas lesions of the neuromuscular junction may be associated with preserved reexes, despite low muscle tone and weakness.8,9 3. Contribution of genetic disorders to the hypotonic infant In the present discussion, we assume that all acute and acquired disorders have been excluded (sepsis, acute infectious


Legend MC- motor cortex


BG-basal ganglia C-cerebellum RF-reticular formation



Upper motor neuron Spinal cord

LVN -lateral vestibular nucleus AHC-anterior horn cell AMN- alpha motor neuron DGC-dorsal ganglion cell

E F motor efferents I F
Ia, II afferents

GMN-gamma motor neuron IF-intrafusal fibre (muscle spindle)


EF-Extrafusal fibre


motor efferents Lower Motor Unit

Figure 1. Schematic diagram of anatomical pathways involved in the regulation of muscle tone. Key structures/pathways of the upper motor neuron and lower motor unit are outlined. The resting state of contraction is determined by alpha motor neuron output which is modied by afferent input from the muscle spindle through the dorsal ganglion cell (DGC) and supraspinal pathways from the motor cortex (MC), reticular formation (RF) and the vestibular nuclei (VN), cerbellum (C) and basal ganglia (BG). AMN, alpha motor neuron; AHC, anterior horn cell; GMN, gamma motor neuron; EF, extrafusal muscle ber; IF, intrafusal muscle ber.

A.N. Prasad, C. Prasad / Seminars in Fetal & Neonatal Medicine 16 (2011) 99e108


4. Evaluation of the hypotonic infant: genetic and metabolic etiologies The assessment should include at least a three-generation pedigree and documentation of prenatal risk factors; a history of drug or teratogen exposure (alcohol, solvents, drugs), breech presentation, reduced fetal movements, presence or absence of polyhydramnios and maternal diseases (diabetes, epilepsy). A family history of recurrent infantile deaths may be signicant the context of congenital myasthenic syndromes.12 The importance of parental age, consanguinity, a family history of neuromuscular disease and the identication of other affected siblings or relatives can provide clues to genetic etiology. Details of any perinatal insults (birth trauma, birth anoxia, delivery complications), low Apgar scores (lower scores for tone, reexes, and respiratory effort), and onset of the hypotonia should be carefully recorded. The length of the umbilical cord, and abnormal fetal presentation reect poor fetal movement or immobility. 5. Clinical examination 5.1. Genetic aspects A careful and systematic examination is an essential next step in establishing an etiological diagnosis. Whereas examination for dysmorphic features is a challenge in the neonatal intensive care units owing to all the various kinds of tubings, tapes, devices etc., the presence of typical craniofacial dysmorphic features can certainly assist in the clinical diagnosis of several conditions, e.g. the features in trisomy 21 (attened posterior occiput, brachycephaly, at nasal bridge, upslanting palpebral ssures, short neck with excess nuchal folds) and the PradereWilli syndrome (almondshaped eyes, frontal narrowing, small hands) can be diagnostic. Eye examination particularly to look for cataracts (peroxisomal disorders), pigmentary retinopathy (peroxisomal disorders) and lens dislocation (sulte oxidase/molybdenum cofactor deciency) is essential. Abnormal fat pads and inverted nipples can point to congenital disorders of glycosylation (CDG). Cardiac enlargement and signs of cardiac failure are seen in infants with Pompe disease. Bilateral 2/3 toe syndactyly should prompt further assessment for SmitheLemlieOpitz syndrome (SLOS). Visceral enlargement (hepatomegaly with or without splenomegaly) suggests storage disorders, and the presence of renal cysts on ultrasound (peroxisomal disorders) is an additional abnormality to look for in the hypotonic infant.6,10 5.2. Neurological assessment A maternal account of reduced fetal movements and the presence of polyhydramnios are often clues that suggest the presence of fetal neuromuscular disorders.13 The presence of a typical myopathic facies, and paucity of facial expression are common in hypotonic infants. A high arched palate is often noted in infants with neuromuscular disorders, and an enlarged tongue suggests storage disorders (acid maltase/Pompe disease). The presence of

Figure 2. (A, B) The typical posture adopted by a hypotonic infant (Pompe disease) in the supine position with the hips abducted and limbs externally rotated. When traction is delivered to the upper limbs during the pull-to-sit maneuver, the head lag is demonstrable. (Reproduced from Prasad AN, Prasad C. The oppy infant: contribution of genetic and metabolic disorders. Brain Dev 2003; 25: 457e76, with permission from Elsevier).

encephalopathies, hypoxiceischemic encephalopathy, trauma, drug-induced states). Clinically relevant conclusions can be drawn from studies published using a systematic approach to elucidating etiologies for the oppy infant (Table 1). First, central hypotonia is more common than peripheral hypotonia in relative terms (60e80% central hypotonia vs 15e30% peripheral).11 Second, using a systematic approach a denitive diagnosis can be established in a signicant proportion of patients (67e85%).6 In an analysis of 277 patients from three clinical series, genetic chromosomal disorders accounted for 31% of the elucidated diagnoses, structural brain anomalies were present in 13%, myopathies in 5%, congenital myotonic dystrophy in 4%, spinal muscular atrophy in 2%, muscular dystrophy in 2% and inborn errors of metabolism in 3%).5e7 Together, geneticemetabolic etiologies account for up to 60% of the cases presenting with hypotonia.
Table 1 Clinical case series on patients with hypotonia: genetic contributions. Published clinical case series in hypotonia Birdi et al.5 Paro-Panjan and Neubauer6 Richer et al.7 Vasta et al.13 Laugel et al.20 Total no. of patients 60 138 50 83 144 Central:peripheral 58:12 121:13 33:17 44:39 98:22

Genetic syndromes 28 70 13 8 (9.6%) 31 (26%)

Inborn errors of metabolism 0 8 0 8 (9.6%) 11 (9%)

Setting University childrens hospital University childrens hospital Neonatal intensive care Neuromuscular unit Tertiary care


A.N. Prasad, C. Prasad / Seminars in Fetal & Neonatal Medicine 16 (2011) 99e108

tongue fasciculation suggests anterior horn cell involvement and denervation. Examination of eye movements can indicate the presence of ptosis and external ophthalmoplegia (congenital myasthenic syndromes). Weakness is easily detected in the presence of a low-pitched cry or a progressively weaker cry, readily distinguished from the vigorous cry of a normal infant. Lack of antigravity movements in the hypotonic infant is a sensitive and specic sign for neuromuscular disorders. Other features such as respiratory problems, recurrent apneas, feeding difculties, and joint contractures have been found to be neither sensitive nor specic for central or peripheral group of disorders.13 Examination of the mother for signs of myotonia is particularly helpful in the diagnosis of congenital myotonic dystrophy (CMD). Cold-induced muscle paralysis or stiffness in older individuals may be suggestive of paramyotonia.14 An established family history of neuromuscular disease may permit the clinician directly to proceed to molecular diagnosis, for instance in cases of congenital myotonic dystrophy, and peripheral neuropathies (e.g. CharcoteMarieeTooth CMT1A).8 Arthrogryposis multiplex congenita (AMC), which refers to the xed position and limitation of joint mobility affecting both proximal and distal joints, is a component of several neurological disorders. Severe weakness early in fetal development immobilizes joints, resulting in contractures. Arthrogryposis thus can be encountered in both neurogenic and myopathic disease. Neurogenic forms of arthrogryposis are more likely to be associated with a higher incidence of other congenital anomalies (low-set ears, micrognathia, wide at nose, short neck, congenital heart disease, high-arched palate, hypoplastic lungs, and cryptorchidism), as compared to the myopathic forms.15,16 Arthrogryposis multiplex congenital (AMC) is also reported in association with Rapsyn mutations in congenital myasthenic syndromes.17 Congenital myasthenic syndromes (CMS) deserve separate mention, as this group seems to be less frequently identied in most published clinical series.18 In part, this is attributable to early presentations that are often indistinguishable from other causes of hypotonia. Infants with CMS are known to present with symptoms of feeding difculties, poor suck and cry, choking spells, arthrogryposis and respiratory insufciency with sudden apnea and cyanosis. Repeated apneic episodes and respiratory crises should be considered as red ags for this group of disorders. In many instances an initial misdiagnosis of a congenital myopathy or other alternative diagnoses are not uncommon. CMS may not be considered for many years, until the clinical signs of fatigability, and signs such as ptosis, facial and bulbar weakness appear. The occurrence of overlapping features between different disorders has been recognized and incorporated into diagnostic algorithms.6,10 Another example of an overlap is that of severe hypotonia associated with lactic acidosis in neonates presenting with spinal muscular atrophy (SMA)-like phenotype due to SCO2 mutations [cytochrome c oxidase (COX) deciency].19 The SMA phenotype has until recently been only associated with mutations in the SMN (Survival Motor Neuron) gene.

6. Laboratory evaluation 6.1. Genetic and metabolic tests Previous studies suggest that the diagnostic yield can be improved by including a karyotype and cranial imaging in addition to a clinical assessment.5,6,20 A diagnostic algorithm is presented based on prior proposals and established practice (Fig. 3A, B). Newer cytogenetic tests such as array comparative genomic hybridization (array CGH) and second generation sequencing studies (exome sequencing) will enhance and facilitate the genetic

investigation of hypotonia. We discuss below the relative values of different diagnostic modalities. Conventional cytogenetics (a standard karyotype at 500 or 550 band resolution) cannot reliably detect rearrangements of genomic segments smaller than 3e5 million base pairs. The detection rate for chromosomal abnormalities with array CGH with a normal karyotype is in the range of 5e17%, a signicant improvement. The principal limitation of this technique apart from its cost is its inability to detect balanced rearrangements (translocation and inversions). In addition, due to its high sensitivity, a proportion of detected copy number variants may be of unclear clinical signicance. Parental sampling may be required to further delineate the pathogenicity of the changes seen. That being said, array CGH is a powerful diagnostic tool and is replacing both conventional cytogenetics, as well as other labour-intensive techniques such as uorescent in-situ hybridization (FISH) and mutli-telomeric FISH.21e23 DNA-based molecular testing carries advantages in terms of reliability and rapidity with which a specic diagnosis can be established, particularly if the mutation has been well characterized. Many disorders are now being diagnosed on the basis of molecular tests alone or in conjunction with other studies (for example in SMA where EMG may help narrow the phenotype). In other clinical situations, however, the answers may prove elusive despite best efforts. In such instances, sequencing of the exome (which is made up of only the protein-coding sequences) may prove helpful. Exome sequencing is likely to be a reasonable and effective tool to determine disease-causing variants underlying monogenic disorders. The limitations of this technique are the currently high cost, the challenge of genetic heterogeneity, and the presence of polymorphic variants due to differing ethnic backgrounds of patients. Exome sequencing relies heavily on the use of bioinformatics to process information about these variants to assess their pathogenicity.24 When the clinical evaluation suggests a complex multisystem pattern of involvement, the investigative work up should also include screening for inborn errors of metabolism particularly (hypotonia plus, Fig. 3B). These biochemical defects belong to one of three categories: toxic encephalopathies (accumulation of toxic metabolites), energy-decient encephalopathies (inborn errors affecting energy production or utilization), and disorders affecting the intracellular processing of complex molecules. The laboratory evaluation for metabolic disorders includes: assays for ammonia, which may be elevated in urea cycle defects, organic acidemias or fatty acid oxidation disorders. High lactate levels in blood and other body uids such as CSF accompany disorders of carbohydrate metabolism and mitochondrial disorders. Other investigations include: quantitative analysis of amino acids in blood and urine (aminoacidopathies), urine organic acids, acylcarnitine proles in the plasma using tandem MS-MS (organic acidemias, fatty acid oxidation defects), assays of very long chain fatty acids (VLCFA) in plasma (peroxisomal disorders), uric acid (normal in sulte oxidase deciency and low in molybdenum cofactor deciency), isoimmune electrophoresis for transferrin [abnormal pattern in disorders of congenital disorders of glycosylation (CDG)] and 7dehydrocholesterol (elevated in SLOS). These tests permit the detection of abnormal metabolites that are biochemical markers for known metabolic disorders with hypotonia. Newborn screening using tandem mass spectrometry can expedite the diagnosis of many small molecule diseases such as some of the urea cycle disorders, fatty acid oxidation disorders, and organic acidemias. A number of centres are now considering the identication of lysosomal disorders through newborn screening. This is particularly important for the early detection of conditions such as infantile Pompe disease, a treatable condition presently by enzyme replacement therapy (myozyme).

Figure 3. (A) Suggested schema for the laboratory evaluation of an infant with central or peripheral hypotonia with the different paths ending in a careful selection of genetic tests to establish diagnosis (box with bold highlighting). (B) Suggested schema for the laboratory evaluation of an infant where the clinical features suggest hypotonia with multisystem manifestations with a focus on selection of appropriate biochemical tests. MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; CMT, CharcoteMarieeTooth; EMG, electromyography; SMN, Survival Motor Neuron; RNS, repetitive nerve stimulation; SMA, spinal muscular atrophy; CGH, comparative genomic hybridization; SNRPN, small nuclear ribonucleoprotein polypeptide N; MS-MLPA, methylation-specic multiplex ligation-dependent probe amplication; AChR, acetylcholine receptor; CHAT, choline acetyltransferase; CNS, central nervous system; PDH, pyruvate dehydrogenase; VLCFA, very long chain fatty acids; WBC, white blood cells; EM, electron microscopy.


A.N. Prasad, C. Prasad / Seminars in Fetal & Neonatal Medicine 16 (2011) 99e108

Well-known genetic syndromes and disorders commonly associated with clinically signicant hypotonia and encountered in clinical practice are listed in Table 2. This list of disorders associated with hypotonia is not meant to be exhaustive or comprehensive, as newer genotypeephenotype relationships continue to be described and syndromes are delineated.25e27 We recommend the use of excellent databases available online through PubMed resources or commercially available websites, e.g. London Medical Databases [WBDD (Winter-Baraitser Dysmorphology Database), and BWND (Baraitser-Winter Neurogenetics Database)]. The former can guide the clinician with pertinent clinical details, whereas the latter enable the clinician to generate a differential diagnosis based

on clinical features. The directory of gene testing laboratories accessed through the National Center for Biotechnology Information (NCBI) website can guide the clinician towards appropriate selection of genetic tests for specic conditions, as well as provide up-to-date information on clinically accredited laboratories performing the tests. The information is being continually updated as more tests and laboratories performing them become available (Table 3). 6.2. Electroneuromyography The technique of electroneuromyography (EMG/nerve conduction study) retains relevance in the investigation of disorders of the lower motor unit. Although earlier technical challenges precluded their use in very young infants, they remain valuable for two reasons: rst, they can help categorize central from peripheral hypotonia; second, nerve conduction and EMG studies are very helpful in distinguishing between a peripheral neuropathy and a motor neuronopathy.28,29 Electromyographers have to be aware of age-related maturational changes in the nerve conduction velocities and size of the motor unit potentials. However, it must be borne in mind that while considering the diagnosis of congenital myopathies in young infants, an EMG lacks specicity and may even be reported as normal, and a muscle biopsy becomes essential. In congenital myasthenic syndromes the results of repetitive nerve stimulation (RNS) show an electrodecrement of >10% in the amplitude of the compound muscle action potential (CMAP) suggesting a block in neuromuscular transmission. As this nding may be technically difcult to demonstrate, a newer technique called the stimulation single ber EMG (StimSFEMG) is being used currently in specialized neuromuscular units. The demonstration of an abnormal jitter is considered to be the most sensitive indicator of a block in neuromuscular transmission. The details of the technique and its limitations have been reviewed recently.12 Once the localization of the defect is known within the motor unit, the clinician has the option of proceeding with a muscle biopsy (myopathy or muscular dystrophy) or directly to molecular genetic testing for relevant inherited neuropathies. If the muscle biopsy provides non-specic ndings suggestive of a myopathy or is reported as normal, molecular testing for congenital myasthenic syndromes should be considered. 6.3. Muscle biopsy in the diagnosis of hypotonic infant A muscle biopsy tends to be an invasive procedure, and as it leaves a scar, it is often selected later in the diagnostic ladder for the algorithms that have been developed. A positive muscle biopsy can be very specic for several congenital myopathies.5,30 A muscle biopsy should include tissue for histopathology, electron microscopy, and respiratory chain studies. Proper tissue handling is essential for specialized assays. 6.4. Cranial imaging in diagnosis of hypotonic infant While MRI technology has largely superseded the use of cranial computed tomography (CT) scans, in certain situations CT scan can be very helpful in the detection of intracranial calcications in disorders such as AicardieGoutieres syndrome.31 This condition is due to links in nucleic acid metabolism with immunity and overlaps with TORCH infections. Careful interpretation of cranial MRI with the help of an experienced neuroradiologist can provide valuable diagnostic clues; cerebellar abnormalites in CDG, molar tooth sign in Joubert syndrome and agenesis of corpus callosum in pyruvate dehydrogenase complex deciency and other metabolic disorders.32e35

Table 2 Hypotonia and etiologies based on previous published series. Category Central hypotonia (normal brain, normal myelination) Differential diagnosis  Non-syndromic mental retardation  Specic: recognizable category of neuronal migration disorders: lissencephaly, holoprosencephaly agenesis of corpus callosum, Joubert syndrome  Unclassiable cerebral anomalies (cerebral dysgenesis)  Leukoencephalopathies Specic: PelizeuseMerzbacher Non-specic: delayed myelination Genetic and chromosomal disorders                     Down syndrome PradereWilli syndrome Fragile X syndrome Trisomy 18 (Edwards syndrome) 1p36 deletion syndrome 22q13 deletion syndrome 22q11.2 deletion syndrome (velocardiofacial/DiGeorge syndrome) Williams syndrome Trisomy 13 (Patau syndrome) SmitheMagenis syndrome Sotos syndrome WolfeHirschhorn syndrome Kabuki syndrome Cri du chat syndrome Anterior horn cell (SMA and variants) Peripheral nerve (CMT 1A, 1B, 2B, 4A, CMTX) Congenital myasthenic syndromes (RAPSN, DOK, COLQ, CHAT) Congenital myopathies (nemaline, central core, etc.) Congenital muscular dystrophies with brain involvement (FCMD, MEB, WWS) Congenital muscular dystrophy without brain involvement (partial merosin deciency, FKRP) Congenital myotonic dystrophy Disorders of glycogen metabolism Acid maltase deciency Severe neonatal phosphofructokinase deciency Severe neonatal phosphorylase deciency Debrancher deciency Primary carnitine deciency Peroxisomal disorders Neonatal adrenoleukodystrophy Cerebrohepatorenal syndrome (Zellweger) Disorders of creatine metabolism Mitochondrial myopathies Cytochrome c oxidase deciency

Central hypotonia (CNS malformations)

Motor unit hypotonia

Metabolic disorders


A.N. Prasad, C. Prasad / Seminars in Fetal & Neonatal Medicine 16 (2011) 99e108 Table 3 Selected disorders presenting in the neonatal period/infancy with hypotonia as one of the main features (with known genetic and metabolic basis). Category Chromosomal anomalies Clinical features Disorder Laboratory testing Karyotype Genetic basis/inheritance Non-disjunction Translocation Mosaicism


Triplet repeat expansion

Hypotonia (100% of infants Down syndrome with Down syndrome have (trisomy 21) hypotonia) Brachycephaly Epicanthal folds Atrioventricular canal defect Hypotonia Fragile X syndrome Prominent jaw Prominent ears

Molecular genetic (FMR1) testing by PCR and/or Southern blot analysis Methylation status of the FMR1 region FMR1 protein assay Array CGH

Microdeletion syndromes

Hypotonia in association with specic phenotypes Facial dysmorphisms Supravalvular aortic stenosis (in Williams syndrome)

Genetic syndromes

Brain anomalies

Anterior horn cell

Hypotonia Overgrowth syndrome Developmental delay Advanced bone age Seizures Hypotonia Seizures Chill blains (AGS) Clinical picture resembling intrauterine infection Typical facies Developmental delay Seizures Retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele Breathing abnormalities Hypotonia Absent peripheral reexes Contractures

1p36 22q13 22q11.2 Williams syndrome SmitheMagenis syndrome WolfeHirschhorn syndrome Sotos syndrome

Triplet repeat expansion causing aberrant hypermethylation of the gene X-Linked dominant inheritance Contiguous gene syndromes

DNA-based testing NSD1 gene sequence analysis Deletion/duplication analysis FISH CT scan: calcication of basal ganglia Increased interferon-a in the CSF, TREX, RNASEH2B gene mutations Cranial MRI FISH testing, deletion testing, and sequence analysis of LIS1 gene Cranial MRI (molar tooth sign) cerebellar and brainstem malformation NPHP1, CEP290, AHI1, and TMEM67 (MKS3) genes (mutations detected in only 10%)

Autosomal dominant >95% of individuals have a de-novo mutation

AGS Lissencephaly MillereDieker syndrome Joubert syndrome

Autosomal recessive/ dominant De-novo deletion in 80% on chromosome 17p13.3 Autosomal recessive

Peripheral neuropathies

Hypotonia Absent reexes

Disorders of neuromuscular transmission

Ptosis Apneas Feeding difculties

Muscle disorders

Myopathic facies Respiratory abnormalities Hypotonia

Hyperammonemias (urea cycle defects)

Encephalopathy Seizures hypotonia (Hypertonia in arginase deciency)

Targeted Mutation analysis for SMN1 gene 95e98% of individuals with SMA are homozygous for the absence of exons 7 and 8 of SMN1 CMT1A, 1B and other Nerve Conduction related conditions DNA-based studies Targeted mutation analysis where available Congenital myasthenic Abnormal repetitive nerve stimulation syndromes Absence of AChR and MuSK antibodies in serum Targeted mutation analysis for mutations in known genes; RAPSN, CHAT, COLQ and AChR subunit Congenital myotonic dystrophy Increased CK expansion of a CTG repeat Congenital muscular dystrophies in the DMPK gene Mutations found in Syndromic 100% of affected individuals Non-syndromic congenital Increased CK, EMG, muscle biopsy, myopathies immuno staining Targeted Mutation analysis for specic known gene defects available for a few syndromic forms of congenital muscular dystrophy a2-Laminin gene mutation Muscle biopsy, EM studies, mutation analysis CPS deciency Ammonia, plasma amino acids, urine OTC deciency amino acids, urine orotic acid, Citrullinemia DNA for mutation analysis Argininoacid lyase deciency Liver biopsy for enzyme analysis Arginase deciency (in rare situations)

Spinomuscular atrophy

Autosomal recessive

Autosomal recessive X-Linked

Autosomal recessive

Triplet repeat expansion (CTG) Autosomal dominant Autosomal recessive

All disorders autosomal recessive (only OTC deciency is X-linked)

(continued on next page)

106 Table 3 (continued ) Category Organic acidemias

A.N. Prasad, C. Prasad / Seminars in Fetal & Neonatal Medicine 16 (2011) 99e108

Clinical features Altered consciousness Hypotonia Metabolic acidosis High ammonia Hypotonia Strabismus Inverted nipples Abnormal fat pads Hypotonia Large tongue Cardiomyopathy

Disorder Propionic acidemia Methylmalonic acidemia

Laboratory testing Ammonia levels, urine organic acids, Lactate, DNA-based mutation studies, Enzyme assay on skin broblasts Transferrin isoform analysis Phosphomannomutase 2 enzyme studies in broblasts DNA mutation studies Cranial MRI-cerebellar atrophy CK Acid maltase enzyme (can be done on lter paper) Urinary tetrasaccharide DNA-based mutation analysis Reduced (<10% of normal) activity of inositol polyphosphate 5-phosphatase OCRL-1 in cultured skin broblasts DNA mutation studies Low uric acid in molybdenum cofactor deciency (Normal in isolated sulte oxidase deciency) Urine for sulfocysteine DNA-based testing for mutations for both conditions Galactocerebrosidase (GALC) enzyme activity is decient (0e5% of normal activity) in leukocytes isolated from whole heparinized blood or in cultured skin broblasts. DNA-based mutation studies Cranial MRI White matter changes Urinary oligosaccharides Skin broblast for enzyme activity b1-Galactosidase Cranial MRI DNA-based mutation studies

Genetic basis/inheritance Autosomal recessive

Pre-lysosomal (congenital disorders of glycosylation)

Jaeken syndrome

Autosomal recessive

Glycogen storage disorder (and lysosomal storage disorder)

Pompe disease (acid maltase deciency)

Autosomal recessive

Lowe syndrome

Hypotonia Cataracts Glaucoma Renal tubular acidosis Molybdenum cofactor deciency Seizures and isolated sulte oxidase Hypotonia deciency Lens dislocation

Lowe syndrome


Autosomal recessive

Leukodystrophies (Krabbe disease)

Hypotonia/peripheral hypertonia Seizures Blindness Irritability

Krabbe disease

Autosomal recessive

Storage disorder (GM1 gangliosidosis)

Disorders of creatine metabolism

Hypotonia Nystagmus Organomegaly Coarse facies Full forehead Flat nose Cherry red spot in retina (50%) Developmental delay Seizures

GM1 gangliosidosis

Autosomal recessive

GAMT deciency Creatine transporter deciency

Mitochondrial myopathies

Hypotonia Seizures (Multisystemic involvement) SMA-like phenotype can occur with COX deciency

(Cytochrome c oxidase deciency) (COX deciency)

Cranial MRS Measurement of guanidinoacetate, creatine, and creatinine in urine and plasma and molecular genetic testing of the three genes involved (GAMT, GATM, or SLC6A8) Lactic acidosis Muscle biopsy: COX-negative bers DNA-based mutation studies Cranial MRI: basal ganglia changes

Autosomal recessive X-linked (creatine transporter deciency)

Autosomal recessive Maternal inheritance (some of the other mitochondrial myopathies)

PCR, polymerase chain reaction; CGH, comparative genomic hybridization; FISH, uorescent in-situ hybridization; AGS, AicardieGoutire syndrome; CMT, Charcot- MarieTooth; CT, computed tomography; CSF, cerebrospinal uid; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; SMA; spinal muscular atrophy; AChR, acetylcholine receptor; CHAT, choline acetyltransferase; MuSK; muscle-specic kinase; CK, creatine kinase; EMG, electromyography; EM, electron microscopy; CPS; carbamylphosphate synthetase; OTC; ornithine transcarbamylase; GAMT; guanidinoacetate methyltransferase; COX, cytochrome c oxidase. Clinical information was accessed through the online databases at the National Center for Biotechnology Information (NCBI): Online Mendelian Inheritance in Man (OMIM) and GeneTests.

Magnetic resonance spectroscopy (proton-MRS) permits the non-invasive assessment of neuronal integrity (N-acetyl aspartate peaks), intracerebral accumulation of unusual metabolites (lactate, glycine) or the deciency of a key metabolite (creatine deciency).36,37 Imaging studies permit the identication of specic patterns of signal abnormalities that may be diagnostic or suggestive of certain disorders (mitochondrial disorders, leukoencephalopathies, leukodystrophies).38e40 These ndings complemented by biochemical screening tests can often be helpful in pointing towards a specic organelle dysfunction.

7. Therapeutic aspects It has been only in recent years that discussions on therapeutic aspects have started to be considered in this kind of review. The treatment approaches for genetic disorders resulting in hypotonia are mostly symptomatic and supportive. Specic interventions such as anticholinesterase inhibitors and 3,4-diaminopyridine are currently in use for the treatment of congenital myasthenic syndromes (CMS), while ephedrine is being tried for CMS associated with DOK7 mutations. The epigenetic modifying

A.N. Prasad, C. Prasad / Seminars in Fetal & Neonatal Medicine 16 (2011) 99e108


effects of valproic acid have been effective in animal models of SMA in improving survival and function and have been tried in patients in initial trials.41,42 Various trials for the treatment of SMA through the use of histone deacetylase inhibitors such as phenylbutyrate have been unhelpful. The use of hydroxyureas may enhance splice function and increase nuclear gems (small nuclear organelles).43 The future of antisense oligonucleotide therapy in the realm of congenital muscular dystrophy remains speculative at present. The timely delineation of an accurate diagnosis for urea cycle defects, fatty acid oxidation disorders and organic acidemias will allow dietary manipulations and use of specic medications. Another important disorder presenting with hypotonia is Pompe disease where early detection and use of myozyme can help with the course.44 There are challenges with cross-reactive immunological material (CRIM)-negative status where more extensive immunomodulation treatment may be required.45 Nevertheless focus has now begun on early detection through newborn screening of Pompe disease in some countries, notably Taiwan.46 Understanding the genomeeproteomeemetabolome relationships will enable the development of animal models as well as the development and screening of compounds to treat at least a few of these complex disorders. Gene therapy remains a distinct possibility in the future. Multidisciplinary supportive management should include orthopedic assessments for hip and other dislocations, physiotherapy, occupational therapy, speech therapies, attention to vision and hearing, as well as psychosocial supports for caregivers and families. 8. Summary The evaluation of a hypotonic infant has to be comprehensive, and on the basis of current evidence requires a multidisciplinary approach. Genetic disorders contribute to more than a third of all disorders leading to hypotonia in early life. As a number of these conditions are inherited, a specic diagnosis of a genetic disorder can outline the prognosis, aid in genetic counseling for the family and provide for carrier testing, prenatal diagnosis as well as preimplantation genetic diagnosis in certain rare situations. Care of the hypotonic infant requires multidisciplinary interventions, and at times is challenging. When considering treatments for formerly progressive conditions such as spinal muscular atrophy, ethical considerations become extremely important. Psychosocial supports for families and involvement in parent support groups should be considered.

Research directions  The role and utility of newly emerging genetic technologies, their clinical applications in the genetic assessment and evaluation of the hypotonic infant.  The neurological and genetic basis of benign essential hypotonia needs to be explored.  Therapies, both disease-specic (as in several myopathies and dystrophies) and those designed to support care and mobility of hypotonic infants, need to be developed.  Research into the physiology of feeding and appropriate interventions to address feeding problems.  Additional research needs to be undertaken into the outcome of infants with different disorders, and into the ethical aspects of care of such infants.

Acknowledgements We would like to thank our patients and their families for teaching us many facets of hypotonia in a newborn/infant. We are grateful to our teachers, students and members of our professional teams for expanding our knowledge of hypotonia. We thank C. Campbell MD, FRCPC, Associate Professor, Department of Pediatrics, University of Western Ontario, for his thoughtful review of the manuscript, valuable comments and suggestions. Conict of interest statement None declared. Funding sources None. References
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Practice points  The evaluation of a hypotonic infant should be multidisciplinary; involving a geneticist, pediatric neurologist, and consultation with pediatric neuroradiologist.  Central hypotonia is more common than peripheral hypotonia.  Geneticemetabolic disorders contribute to more than 50% of cases of hypotonia in the newborn and infancy.  Weakness of antigravity movements associated with hypotonia is the most sensitive clinical marker for neuromuscular disorders.  A combination of careful clinical examination, cranial imaging, and appropriately selected genetic tests can lead to a diagnosis in up to 60% of infants presenting with hypotonia.  In selected cases with multisystem involvement, additional biochemical evaluations should be undertaken in consultation with a metabolic geneticist.


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