Congenital Hypotonia in Toddlerhood.

CASE: David is a 22-month-old boy who is new to your practice. He recently moved from a rural area in the Midwest. His father is in the United States Air Force, and his mother works as a full-time homemaker. Their household includes 5 older siblings. The family moves every year because of the father's Air Force placement.David was born full-term in Virginia, with no reported pregnancy complications and no alcohol, tobacco, or drug exposure. He was delivered vaginally, with Apgar scores of 7 and 9, respectively and no respiratory issues. In the newborn nursery, his nurse noted that he was floppy, with generalized low muscle tone. Laboratory work performed included normal thyroid studies and a chromosomal microarray.Because of persistent hypotonia, he was seen by a pediatric neurologist at 9 months of age. A magnetic resonance imaging was performed and was normal, with no structural deficits noted. He was referred to Early Intervention at 6 months, when he was not yet rolling over. He received physical therapy for a few months before the family moved again for his father's next placement.David presents in your office as a sweet nondysmorphic toddler who maintains steady eye contact and smiles responsively. His height, head circumference, and weight are at the 50th percentile. His physical examination is notable for generalized hypotonia, with intact upper and lower deep tendon reflexes. He spontaneously says about 20 words. He turns his head when his name is called and can follow a simple command, such as "clap, clap." He reaches his whole hand toward desired objects and will look at his parents if they are out of reach. He can grasp a block, bang, and transfer objects. He demonstrates an immature pincer grasp. He can roll over and sit independently and is just beginning to pull to a stand. His parents report he has recently restarted Early Intervention, where he is receiving physical, speech, and occupational therapy. His audiology examination is normal.His parents' primary concern today is regarding feeding. David is a picky eater. He has difficulty with new foods and textures. The parents noticed a regression in his tolerance for new foods around the recent move. He eats baby puffs, stage 2 to 3 baby foods, and fruit and vegetable pouches. He does not like soft, sticky foods. He is also reported to have other sensory sensitivities. He does not tolerate loud noises and is bothered by tags in his clothing. You wonder, what further work-up would be helpful for David? How can his feeding issues be addressed?

Enfermedad renal por depósito idiopático de cadenas livianas. Caso clínico / Kidney involvement in idiopathic light chain disease. Report of one case

El Mieloma Múltiple (MM) es la gammapatia monoclonal (GM) que más frecuentemente compromete la función renal, no obstante, un número creciente de enfermedades renales asociadas a GM están siendo reconocidas. Las GM son un conjunto de entidades caracterizadas por la producción anómala y secreción a la sangre de una inmunoglobulina (Ig) monoclonal (de un mismo clon de células plasmáticas) o un fragmento de la misma (cadenas pesadas, ligeras o ambas) que puede depositarse en los órganos de forma organizada como cristales, fibrillas o microtúbulos, o de forma no organizada (granular). Esta Ig llega a depositarse principalmente en el riñón, no sólo porque es un órgano muy vascularizado, sino también porque el túbulo renal tiene un papel predominante en el metabolismo de las Igs. El diagnóstico del compromiso renal ha sufrido cambios en las últimas décadas, siendo cada vez más certero debido al desarrollo e implementación rutinaria de distintas técnicas de laboratorio (tinciones con anticuerpos específicos contra cadenas ligeras kappa y lambda, estudio con microscopia electrónica (ME) y el desarrollo de técnicas cada vez más sensibles para detectar el componente monoclonal en sangre u orina). El compromiso renal en estas patologías frecuentemente se asocia a GM malignas, generalmente asociadas a depósitos de cadenas ligeras. Cada vez son más los casos de disfunción renal asociados a GM, y en muchos de estos es evidente el progreso a enfermedad renal terminal y con altas tasas de recurrencia después del transplante renal.

Multiple myeloma (MM) is the monoclonal gammopathy (MG) that most frequently compromises renal function; however, a growing number of renal diseases associated with monoclonal gammopathies are being recognized. Monoclonal gammopathies (MG) are a set of entities characterized by the abnormal production and secretion into the blood of a monoclonal immunoglobulin (Ig) from a single clone of plasma cells or a fragment thereof (heavy, light chains orboth) which can be deposited in the organs in an organized way such as crystals, fibrils or microtubules, orin an unorganized (granular) form. This Ig is mainly deposited in the kidney, not only because it is a very vascularized organ, but also because the renal tubule plays a predominant role in the metabolism of Igs. The diagnosis of renal involvement has undergone changes in the last decades, being more and more certain due to the development and routine implementation of different laboratory techniques (stains with specific antibodies against kappa and lambda light chains, study with electron microscopy (EM), development of increasingly sensitive techniques for detecting the monoclonal component in blood or urine). Renal involvement in these pathologies is often associated with malignant MG, generally associated with light chain deposits. Increasingly, there are cases of renal dysfunction associated with MG, and progression to terminal renal disease and high rates of recurrence after renal transplantation are evident in many of these.

CDC174, a novel component of the exon junction complex whose mutation underlies a syndrome of hypotonia and psychomotor developmental delay.

Siblings of non-consanguineous Jewish-Ethiopian ancestry presented with congenital axial hypotonia, weakness of the abducens nerve, psychomotor developmental delay with brain ventriculomegaly, variable thinning of corpus callosum and cardiac septal defects. Homozygosity mapping identified a single disease-associated locus of 3.5 Mb on chromosome 3. Studies of a Bedouin consanguineous kindred affected with a similar recessive phenotype identified a single disease-associated 18 Mb homozygosity locus encompassing the entire 3.5 Mb locus. Whole exome sequencing demonstrated only two homozygous mutations within a shared identical haplotype of 0.6 Mb, common to both Bedouin and Ethiopian affected individuals, suggesting an ancient common founder. Only one of the mutations segregated as expected in both kindreds and was not found in Bedouin and Jewish-Ethiopian controls: c.1404A>G, p.[*468Trpext*6] in CCDC174. We showed that CCDC174 is ubiquitous, restricted to the cell nucleus and co-localized with EIF4A3. In fact, yeast-two-hybrid assay demonstrated interaction of CCDC174 with EIF4A3, a component of exon junction complex. Knockdown of the CCDC174 ortholog in Xenopus laevis embryos resulted in poor neural fold closure at the neurula stage with later embryonic lethality. Knockdown embryos exhibited a sharp reduction in expression of n-tubulin, a marker for differentiating primary neurons, and of hindbrain markers krox20 and hoxb3. The Xenopus phenotype could be rescued by the human normal, yet not the mutant CCDC174 transcripts. Moreover, overexpression of mutant but not normal CCDC174 in neuroblastoma cells caused rapid apoptosis. In line with the hypotonia phenotype, the CCDC174 mutation caused depletion of RYR1 and marked myopathic changes in skeletal muscle of affected individuals.

MED12 mutations in human diseases.

The Mediator Complex plays key roles in activating gene transcription in eukaryotes. Mediator of RNA polymerase II transcription subunit 12 homolog (MED12) is a subunit of the Mediator Complex and regulates the activity of the complex. MED12 is involved in a variety of cellular activities, and mutations in MED12 gene impair MED12 activities and are associated with several diseases, including Opitz-Kaveggia syndrome, Lujan syndrome, uterine leiomyomas and prostate cancer. This review will discuss the biological function of MED12 and the relationship between MED12 mutations and diseases.

The hypothetical role of congenital hypotonia in the development of early coronoid hyperplasia.

BACKGROUND: Coronoid hyperplasia (CH) is an abnormal bony elongation of a histologically normal coronoid process. Its definitive cause remains unknown. OBJECTIVES: To analyze the possible implication of congenital hypotonia in the pathogenesis of early coronoid overgrowth. PATIENTS AND METHODS: Two infants with congenital hypotonia were evaluated for limited mouth aperture. Bilateral CH was diagnosed. Transoral coronoidectomy was followed by an early dynamic physiotherapy program. RESULTS: Significant improvement of maximum interincisal opening was achieved. The review of the scientific literature proved the diagnosis of CH in the infant age group is extremely unusual and the etiology of the condition is still uncertain. CONCLUSIONS: Besides mouth opening restriction, clinical features of coronoid hyperplasia in infants can include suction or deglutition anomalies, failure to thrive and recurrent episodes of choking or aspiration pneumonia. The authors hypothesize reduced fetal mandibular movements and deglutition as a result of congenital hypotonia may lead to relative hyperactivity of the temporalis muscle that is not counterbalanced by the infra and suprahyoid muscles, thereby facilitating coronoid overgrowth.

Branching enzyme deficiency/glycogenosis storage disease type IV presenting as a severe congenital hypotonia: muscle biopsy and autopsy findings, biochemical and molecular genetic studies.

The fatal infantile neuromuscular presentation of branching enzyme deficiency (glycogen storage disease type IV) due to mutations in the gene encoding the glycogen branching enzyme, is a rare but probably underdiagnosed cause of congenital hypotonia. We report an infant girl with severe generalized hypotonia, born at 33 weeks gestation who required ventilatory assistance since birth. She had bilateral ptosis, mild knee and foot contractures and echocardiographic evidence of cardiomyopathy. A muscle biopsy at 1 month of age showed typical polyglucosan storage. The autopsy at 3.5 months of age showed frontal cortex polymicrogyria and polyglucosan bodies in neurons of basal ganglia, thalamus, substantia innominata, brain stem, and myenteric plexus, as well as liver involvement. Glycogen branching enzyme activity in muscle was virtually undetectable. Sequencing of the GBE1 gene revealed a homozygous 28 base pair deletion and a single base insertion at the same site in exon 5. This case confirms previous observations that GBE deficiency ought to be included in the differential diagnosis of congenital hypotonia and that the phenotype correlates with the 'molecular severity' of the mutation.

I-Z-I complexes in congenital myopathy.

A 3-month-old boy with hypotonia at birth succumbed to a congenital myopathy. The major finding in his muscle biopsy corresponded to I-Z-I complexes described previously in embryonic skeletal muscle. A few previous myopathy cases have described findings suggestive of I-Z-I-like complexes. A mutation affecting mononuclear myoblasts or early myotubes was suspected, although an acquired lesion could not be ruled out. The findings may also have been altered by secondary events in this unusual case.

[Nemaline myopathy as a cause of neonatal hypotonia - with emphasis on personal experiences. Report of a family with two brothers affected]. / Miopatia nitkowata jako przyczyna wiotkosci u noworodka, z uwzglednieniem wlasnych badan. przypadek rodzinny u 2 braci.

Nemaline myopathy is a heterogenous form of congenital myopathy characterised by a variable spectrum of clinical features, predominated in the severe form by profound muscle hypotonia and weakness accompanied by respiratory insufficiency. The clinical variability, with differing age of onset and severity of symptoms makes the diagnosis of nemaline myopathy difficult in some cases. Severe forms of nemaline myopathy may be caused by mutation of a number of different genes: skeletal muscle actin (ACTA1), nebulin (NEB) and alpha-tropomyosin (TPM3), all of which encode components of the sarcomeric thin filaments of skeletal muscle. We describe the severe form of nemaline myopathy diagnosed in two brothers who died at the age of 12 days and 9 months, due to respiratory insufficiency caused by severe muscle weakness. Polyhydramnios and weakness of foetal movements in the IIIrd trimester of pregnancy, as well as variable clinical severity were noted in both cases. Microscopically visible significant immaturity of muscle fibers was found in the skeletal muscle biopsy performed in one of the brothers. The diagnosis of nemaline myopathy was confirmed by the presence of nemaline bodies (rods) in sections stained using the Gomori trichrome method. Molecular studies of DNA isolated from blood leucocytes showed no mutation in the ACTA1 or the TPM3 genes. Linkage analysis with polymorphic markers did not rule out linkage to part of the NEB gene locus. Results of the clinical evaluation and the investigations performed in the family members confirm that it is essential to consider congenital myopathies in the differential diagnosis of neonatal and infantile hypotonia with respiratory insufficiency. Molecular verification of the clinical diagnosis is also important for genetic counselling of the families.

Stuve Wiedemann syndrome and related syndromes: case report and possible anesthetic complications.

Stuve Wiedemann syndrome (SWS) is an autosomal recessively inherited syndrome which is characterized by bowing of the long bones, camptodactyly, facial dysmorphism, hypotonia, feeding and swallowing difficulties, and respiratory distress. In most cases episodes of unexplained hyperthermia are present. Patients with SWS can develop hyperthermia in conjunction with anesthesia and surgery, and a relationship has been suggested between the syndrome and malignant hyperthermia. We describe a 3-year-old child diagnosed with SWS to whom we administered general anesthesia during the removal of a corneal ulcer and dilatation of the lacrimal duct. Our patient had received, uncomplicated, inhalational anesthesia five times previously for different operations. There were no anesthesia-related complications in the present or previous perioperative periods. On one occasion the patient developed mild postoperative hyperthermia. We believe that this hyperthermia is different from the specific disorder of malignant hyperthermia and that sevoflurane can be safely used in patients with SWS. We also describe symptomatically related syndromes and their theoretical risks for anesthesia.

[Cap myopathy: a case report]. / Miopatía en gorra: a propósito de un caso.

AIM: To report a new case of a little-known congenital myopathy. Cap myopathy is a rare congenital disease caused by an alteration in the structure of the fibre, with disorganised myofibrils at the edges. Since it was first described, only a few cases have been reported in the literature. CASE REPORT: We describe the case of a 16-year-old patient with a history of neonatal hypotonia and psychomotor retardation. At the age of 4 years, the patient presented myopathic facies with atrophied pectoral muscles, winged scapula and lumbar hyperlordosis. A myopathic pattern was observed in the electromyogram. A muscle biopsy showed a very marked predominance of type I fibres, atrophy in part of the population of this type and 20% of them had cap-shaped subsarcolemmal accumulations, which were intensely positive with DPNH and SDH; in the ultrastructural study they correspond to disorganised peripheral myofibrils with preservation of the Z band and the absence of A bands. These alterations are similar to those described in what is known as cap disease or cap myopathy. Today, the patient has mild proximal tetraparesis and moderate restrictive respiratory failure.

Síndrome da criança hipotônica: causas neuromusculares / Floppy infant syndrome due to neuromuscular disorders

A síndrome da criança hipotônica engloba as condições em que a hipotonia muscular se manifesta no recém-nascido ou nos primeiros dois anos de vida. Inclui um grande númerode situações que podem ser divididas em dois subtipos: a hipotonia intrínseca ou primária, que depende do acometimento das estruturas que compõem a unidade motora periférica desde o motoneurônio medular até o músculo, e a hipotonia secundária. Esta última ocorre principalmente como sinal acessório em afecções neurológicas com comprometimento do sistema nervoso central, ou no contexto de síndromes genéticas, bem como de doençassistêmicas graves de caráter extraneurológico. Neste trabalho nos referiremos apenas às situações de hipotonia intrínseca, ou seja, doenças neuromusculares, caracterizando asprincipais afecções deste grupo no recém-nascido e no lactente, e enfatizando quais os aspectosclínicos que permitem orientar as hipóteses diagnósticas e indicar os exames complementares adequados, principalmente, os testes moleculares, quando possíveis...

The congenital hypotonia, also known as the floppy infant syndrome, refers to an infant with generalized hypotonia presenting at birth or in early life. The most important aspect to be considered for assessing the diagnosis is to differentiate between a primary cause ofhyptonia due to a neuromuscular disorder and a secondary cause due to non neurological conditions, chromosomal abnormalities or central nervous system involvement (cerebral causes of congenital hypotonia). The focus of the present review are: to report the main neuromuscular disorders, i.e. primary congenital hypotonia, that begin along the first two years of life; to describe the clinical aspects that suggest the differential diagnosis among these entities in order to allow a correct investigation and to avoid unnecessary methods of valuation. It is als o emphasized the value of the molecular diagnosis that is now available for some of these conditions...

Global distribution of the most prevalent deletions causing hypotonia-cystinuria syndrome.

Hypotonia-cystinuria syndrome (HCS) is a recessive disorder caused by microdeletions of SLC3A1 and PREPL on chromosome 2p21. Patients present with generalized hypotonia at birth, failure to thrive, growth retardation and cystinuria type I. While the initially described HCS families live in small regions in Belgium and France, we have now identified HCS alleles in patients and carriers from the Netherlands, Italy, Canada and United States of America. Surprisingly, among the nine deletions detected in those patients, only one novel deletion was found. Furthermore, one previously described deletion was found six times, another twice. Finally, we have investigated the frequency of both deletions using a random Belgian cohort. Given the global occurrence, HCS should be considered in the differential diagnosis of neonatal hypotonia.

Basicranial diplomyelia: an extension of the split cord malformation theory. Case report.

Basicranial diastematomyelia is an extremely rare congenital disorder. A review of the literature indicates only one reported case of basicranial diastematomyelia in which an osseous peg divided the brainstem in two. The authors present the first reported case of basicranial diplomyelia split by a fibrous band and correlate its pathogenesis with that of split cord malformation (SCM). The patient described in the present report had a fibrous stalk dividing the brainstem, and therefore the condition was categorized as a diplomyelia, or SCM Type II. Because the occipital dermatomes behave similarly to the spinal dermatomes early in development, they may be subject to the same embryonic error that results in SCM. The authors propose that the mechanism leading to SCM is the same as that found in basicranial split malformations and that the theory explaining it be modified to include the posterior fossa.

Pallister-Killian syndrome (PKS): clinical case report.

Pallister-Killian Syndrome is a rare dysmorphic condition characterized by specific clinical manifestations and tetrasomy 12p. This paper focuses on the general and orofacial clinical manifestations.

Clinical and histologic changes in the follow-up of a congenital myopathy.

A 19-year-old woman was born with congenital hypotonia, generalized weakness, and dysmorphic features. A muscle biopsy performed at age 18 months found that type I fibers were smaller and more numerous than type II fibers, and she was diagnosed with congenital fiber type disproportion. She grew up with moderate motor impairment, but after a stationary period her weakness progressed gradually and she developed a severe ophthalmoplegia. When she was 18 years old a second muscle biopsy still indicated the predominance of type I fibers but also the presence of central nuclei and strong oxidative enzyme activity in the center of most of the fibers; this was compatible with centronuclear myopathy. The diagnostic reconsideration raises questions about the pathogenesis of these diseases and the recognition of congenital fiber type disproportion as a distinct nosologic entity.

A novel MPZ gene mutation in congenital neuropathy with hypomyelination.

Congenital hypomyelinating neuropathy (CHN; MIM# 605253) is a severe neuropathy with early infancy onset inherited as an autosomal dominant or recessive trait. Sural nerve biopsy shows a characteristic picture of nonmyelinated and poorly myelinated axons with basal lamina onion bulbs and lack of myelin breakdown products. Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been found in patients with CHN. The authors describe the clinical and morphologic features of a patient with CHN and the identification of a novel Thr124Lys mutation in the MPZ gene.

Congenital fiber type disproportion--30 years on.

Thirty years ago, M. H. Brooke coined the term "congenital fiber type disproportion" (CFTD) to describe 12 children who had clinical features of a congenital myopathy and relative type 1 fiber hypotrophy on muscle biopsy. It is now clear that this histological pattern can accompany a wide range of neurological disorders, leading to disillusionment with CFTD as a distinct nosological entity. To determine whether the CFTD has clinical utility as a diagnostic entity, we have reviewed the literature for cases of type 1 fiber hypotrophy and have used strict exclusion criteria to identify 67 cases of CFTD. Most patients presented at birth with weakness and hypotonia, had normal intelligence, and followed a static or improving clinical course. In 43% of families, more than 1 individual was affected. Failure to thrive was common and 25% of patients had contractures or spinal deformities. Bulbar weakness and ophthalmoplegia were less common and cardiac involvement was rare. Twenty-five percent followed a severe course and 10% had died at the time of reporting, all from respiratory failure. Ophthalmoplegia and facial and bulbar weakness were significantly associated with a poorer prognosis. The relatively homogeneous phenotype supports the retention of CFTD as a distinct diagnostic entity and familial occurrence suggests a genetic basis. Regarding the diagnosis of CFTD, we found no strong evidence that the minimum difference between type 1 and type 2 fiber sizes should be increased from 12% to 25%. We also list the other reported causes of relative type 1 fiber hypotrophy to aid their exclusion from CFTD.