Cervical Instability and Quadriparesis Requiring Stabilization in Pediatric Patient Caused by a Mutation in COL2A1.

A 3-year-old male with no past medical history presented with flaccid plegia of his upper extremities and significant weakness in his lower extremities after wrestling with his brother. Cervical spine magnetic resonance imaging was consistent with cord edema and intraparenchymal hemorrhage at C1-C2. A nonossified tissue mass at the expected location of the upper dens created narrowing of the canal at the C1-2 level and mass effect on the cord. Head computed tomography showed periventricular leukomalacia. Initial findings favored dysplasia of the odontoid with associated soft tissue mass/pannus caused by a possible underlying genetic or metabolic bone dyscrasia. The patient underwent suboccipital craniotomy/C1 laminectomy and occiput to C4 fusion, for decompression and stabilization. Genetic testing showed a COL2A1 collagen disorder, with the child harboring a de novo mutation for c.3455 G>T (p.G1152V). The patient was discharged to inpatient acute rehabilitation, with gradual improvement in strength in all 4 extremities.

Progressive cerebral atrophies in three children with COL4A1 mutations.

BACKGROUND: The collagen type IV alpha 1 chain (COL4A1) gene on 13q34 encodes one chain of collagen. COL4A1 mutations have been identified as the cause of a group of multisystemic conditions in humans, including the brain, eyes, kidneys, muscles, and other organs at any age. Brain imaging shows a wide spectrum of abnormalities, including porencephaly, schizencephaly, polymicrogyria focal cortical dysplasia, periventricular leukoencephalopathy, ventricular dysmorphisms, and multiple brain calcifications. However, there are no reports in the literature showing progressive radiological findings in consecutive follow-up scans. Herein, we report three cases of COL4A1 mutations with porencephaly from gestation to five years of age or longer, and describe their clinical and brain imaging findings. CASE REPORTS: We retrospectively reviewed the clinical symptoms and radiological findings, including brain magnetic resonance imaging (MRI) and computed tomography (CT), in three female patients with COL4A1 mutations. Their mutations were c.4843G>A (p.Glu1615Lys), c.1835G>A (p.Gly612Asp), and c.3556+1G>T respectively. All the three cases represented porencephaly in the fetal period; severe hemolytic anemia in the neonatal period; and drug-resistant epilepsy, global developmental delay, and spastic quadriplegia in their childhood. RESULTS: Brain MRI and CT showed progressive white matter atrophy from gestation to five-year follow-up or later. Minor cerebral hemorrhage without symptoms occasionally occurred in one patient. Despite brain changes, the clinical picture was stable during early childhood. CONCLUSIONS: COL4A1 mutations may cause progressive cerebral atrophy beyond early childhood.

West syndrome, developmental and epileptic encephalopathy, and severe CNS disorder associated with WWOX mutations.

Mutations in the WWOX gene have been reported in a number of patients with various neurological disorders including spino-cerebellar ataxia, intellectual disability, epilepsy, and epileptic encephalopathy. We aimed to study the clinical, electrographic, and imaging features of two new cases with WWOX mutations and compare them to previously reported cases with WWOX mutations. We assessed two unrelated children from two consanguineous families who had severe neurological disorder including early-onset spastic quadriplegia, profound developmental delay, epilepsy, and West syndrome. Based on whole-exome sequencing, we identified homozygous null mutations in WWOX in both children, and further addressed the genotype-phenotype correlation. In addition, we provide a detailed review of the previously reported cases of WWOX-related neurological disorders and compare them to the children in this report. The findings in this report expand the clinical phenotype associated with WWOX mutations and confirm a well characterised severe central nervous system disorder in association with biallelic null mutations in WWOX. This syndrome consists of profound psychomotor delay, early-onset spastic quadriplegia, and refractory epilepsy including epileptic encephalopathy, acquired microcephaly, and growth restriction. This can be associated with progressive brain atrophy, suggestive of neurodegeneration. Identification of this phenotype by clinicians may help with early diagnosis and appropriate genetic counselling.

Familial KANK1 deletion that does not follow expected imprinting pattern.

Deletion of the KANK1 gene (also called ANKRD15), located at chromosome position 9p24.3, has been associated with neurodevelopmental disease including congenital cerebral palsy, hypotonia, quadriplegia, and intellectual disability in a four-generation family. The inheritance pattern in this family was suggested to be maternal imprinting, as all affected individuals inherited the deletion from their fathers and monoallelic protein expression was observed. We present a family in which the proband's phenotype, including autism spectrum disorder, motor delay, and intellectual disability, is consistent with this previous report of KANK1 deletions. However, a paternally inherited deletion in the proband's unaffected sibling did not support maternal imprinting. This family raises consideration of further complexity of the KANK1 locus, including variable expressivity, incomplete penetrance, and the additive effects of additional genomic variants or the potential benign nature of inherited copy number variations (CNVs). However, when considered with the previous publication, our case also suggests that KANK1 may be subject to random monoallelic expression as a possible mode of inheritance. It is also important to consider that KANK1 has two alternately spliced transcripts, A and B. These have differential tissue expression and thus potentially differential clinical significance. Based upon cases in the literature, the present case, and information in the Database of Genomic Variants, it is possible that only aberrations of variant A contribute to neurodevelopmental disease. The familial deletion in this present case does not support maternal imprinting as an inheritance pattern. We suggest that other inheritance patterns and caveats should be considered when evaluating KANK1 deletions, which may become increasingly recognized through whole genome microarray testing, whole genome sequencing, and whole exome sequencing techniques.

Association of Interleukin 6 gene polymorphisms with genetic susceptibilities to spastic tetraplegia in males: a case-control study.

BACKGROUND: Cerebral palsy (CP) is a group of non-progressive motor impairment and permanent disorders causing limitation of activity and abnormal posture. It may be caused by infection (such as chorioamnionitis), asphyxia or multiple genetic factors. The Interleukin 6 gene (IL6) was suggested to be involved in the susceptibilities to CP risk as a kind of proinflammatory cytokine. OBJECTIVE: To explore the genetic association between the polymorphisms of the IL6 gene and CP in the Chinese population. METHODS: A total of 542 CP patients and 483 healthy control children were recruited in this study to detect five single nucleotide polymorphisms (rs1800796, rs2069837, rs2066992, rs2069840, and rs10242595) in the IL6 locus. Genotyping of SNPs was performed by the MassArray platform-based genotyping approach. The SHEsis program was applied to analyze the genotyping data. RESULTS: Of the five selected SNPs, no significant allelic and genotypic association was found between CP patients and controls. However, subgroup analysis found significant differences in allele frequencies between spastic tetraplegia in males compared with controls at rs1800796 (OR=1.39, P=0.033, P=0.099 after SNPSpD correction) and rs2069837 (OR=1.58, P=0.012, P=0.035 after SNPSpD correction). The frequencies of the C allele of rs1800796 and the A allele of rs2069837 were greater in males with spastic tetraplegia than in the controls. The two SNPs haplotype rs1800796 (G) - rs2069837 (G) were also associated with a decreased risk of spastic tetraplegia in males (OR=0.619, P=0.009, P=0.027 after Bonferroni correction). CONCLUSION: Genetic variation of the IL6 gene may influence susceptibility to spastic tetraplegia in males and its role in cerebral palsy deserves further evaluation in a large-scale and well-designed study.

[Inclusion body myositis, Paget's disease of the bone and frontotemporal dementia: early involvement of the heart and respiratory muscles]. / Inclusion Body Myositis mit Morbus Paget und frontotemporaler Demenz: frühe Beteiligung des Herzens und der Atemmuskulatur.

Since valosin-containing protein mutations were reported as a cause of hereditary inclusion body myositis associated with Paget's disease of the bone and frontotemporal dementia, many new mutations have been described in the last decade. We report on a 46-year-old German male with a progressive tetraparesis and autosomal dominant inheritance pattern. Echocardiography revealed a beginning dilated cardiomyopathy and laboratory analyses showed increased alkaline phosphatase. Decreased verbal memory and an impairment of concept building were observed on neuropsychological examination. Muscle biopsy demonstrated a myopathic pattern, rimmed vacuoles, CD8+ T-cell infiltrates and positive MHC1-muscle fibres. We found a heterozygote mutation in exon 5 of the valosin-containing protein gene (c.464G > T p.Arg155Leu), which until now has been described only in an Australian family. We describe here the first German case with the above-mentioned mutation causing inclusion-body myositis associated with Paget's disease of the bone and fronto-temporal dementia. Here, we recommend regular controls of cardiac and respiratory functions.

Myofibrillar protein and gene expression in acute quadriplegic myopathy.

The dramatic muscle wasting, preferential loss of myosin and impaired muscle function in intensive care unit (ICU) patients with acute quadriplegic myopathy (AQM) have traditionally been suggested to be the result of proteolysis via specific proteolytic pathways. In this study we aim to investigate the mechanisms underlying the preferential loss of thick vs. thin filament proteins and the reassembly of the sarcomere during the recovery process in muscle samples from ICU patients with AQM. Quantitative and qualitative analyses of myofibrillar protein and mRNA expression were analyzed using SDS-PAGE, confocal microscopy, histochemistry and real-time PCR. The present results demonstrate that the transcriptional regulation of myofibrillar protein synthesis plays an important role in the loss of contractile proteins, as well as the recovery of protein levels during clinical improvement, myosin in particular, presumably in concert with proteolytic pathways, but the mechanisms are specific to the different thick and thin filament proteins studied.

Expanding the neurologic phenotype of oculodentodigital dysplasia in a 4-generation Hispanic family.

We report a 4-generation Hispanic family with oculodentodigital dysplasia whose members were found to have typical phenotypic characteristics of this disorder, as well as a variable expression of neurologic manifestations in multiple generations ranging from a mild spastic gait to moderate to severe spastic tetraparesis/quadriplegia with epilepsy and an abnormal brain and spinal cord magnetic resonance imaging result. Gene testing documented a previously reported missense mutation in GJA1 (connexin 43) exon 2 (c.389T>C;p.I130T). Our evaluation not only expands the phenotypes associated with GJA1 gene mutations but also demonstrates that a great degree of variability in neurological defects can exist within a single family without evidence of genetic anticipation. A genotype-phenotype correlation between the p.I130T mutation and neurologic dysfunction appears more likely with the addition of this report's neurologic and GJA1 gene mutation findings. These findings expand the neurologic phenotype and prognosis and underscore the importance of counseling families with oculodentodigital dysplasia about the possibility of neurologic involvement.

Familial and genetic associations in Worster-Drought syndrome and perisylvian disorders.

Worster-Drought syndrome (WDS) is a distinct clinical phenotype, comprising a congenital pseudobulbar palsy usually in association with a mild tetraplegia and often additional impairments. The phenotype is identical to that described in congenital bilateral perisylvian polymicrogyria syndrome (CBPS) and appears to have several different causes and a significant familial incidence. This study draws from a database of children with WDS phenotype or perisylvian polymicrogyria, held at a tertiary center. The findings suggest that genetic factors are important for a significant proportion of children and points to considerable genetic heterogeneity. There are grounds for considering WDS and perisylvian polymicrogyria as a spectrum of perisylvian malfunction.

Melnick- needles osteodysplasty presenting with quadriparesis.

Melnick-Needles syndrome or osteodysplasty, a monogenic heritable bone dysplasia, is characterized by a typical facies and characteristic radiological findings. Less than 70 well-documented cases have been reported in literature; most of them were sporadic. We report the first case from Eastern India in an adolescent male, who had cranio-vertebral junction anomalies and presented with spastic quadriparesis at the age of 13 years.

Mosaic mutations of the LIS1 gene cause subcortical band heterotopia.

BACKGROUND: Subcortical band heterotopia (SBH) is a neuronal migration disorder. DCX mutations are responsible for almost all familial cases, 80% of sporadic female cases, and 25% of sporadic male cases of SBH, and are associated with more severe gyral and migration abnormality over the anterior brain regions. Somatic mosaicism has previously been hypothesized in a patient with posteriorly predominant SBH and a mutation of the LIS1 gene, which is usually mutated in patients with severe lissencephaly. The authors identified mosaic mutations of LIS1 in two patients (Patients 1 and 2) with predominantly posterior SBH. METHODS: After ruling out DCX mutations, the authors performed sequencing of the LIS1 gene in lymphocyte DNA. Because sequence peaks in both patients were suggestive of mosaic mutations, they followed up with denaturing high-pressure liquid chromatography analysis on blood and hair root DNA and compared the areas of heteroduplex and homoduplex peaks. A third patient showing the same mutation as Patient 2 but with no evidence of mosaicism was used for comparing the phenotype of mosaic vs full mutation. RESULTS: The two patients with posterior SBH harbored a missense (Arg241Pro) and a nonsense (R8X) mosaic mutation of LIS1. The rate of mosaicism in Patient 1 was 18% in the blood and 21% in the hair roots, whereas in Patient 2 it was 24% and 31% in the same tissues. The patient with a full R8X mutation of LIS1 had severe lissencephaly. CONCLUSIONS: Subcortical band heterotopia can occur with mosaic mutations of the LIS1 gene. Mutation analysis of LIS1, using highly sensitive techniques such as denaturing high-pressure liquid chromatography, should be considered for patients with posteriorly predominant subcortical band heterotopia and pachygyria.

Association of the congenital bone marrow failure syndromes with retinopathy, intracerebral calcification and progressive neurological impairment.

We present a child with Fanconi anaemia and congenital hypopituitarism, who developed intracerebral calcifications, progressive spasticity and retinopathy. The chromosome fragility with mitomycin C was increased in both the patient and his sibling, confirming a diagnosis of Fanconi anaemia. Aplastic anaemia in association with intracerebral calcifications has been described in patients with dyskeratosis congenita and Revesz syndrome, but not so far in confirmed cases of Fanconi anaemia. This case further illustrates the greater overlap of associated features in congenital bone marrow failure syndromes. It also indicates that Fanconi anaemia should be actively excluded where such associated features are found.

Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids: mechanisms at the cellular and molecular levels.

OBJECTIVE: Long-term treatment with nondepolarizing neuromuscular blocking agents and corticosteroids in the intensive care unit is not benign, and an increasing number of patients with acute quadriplegic myopathy have been reported with increased use of these drugs. The purpose of this study was to investigate the mechanisms underlying acute quadriplegic myopathy. DESIGN: Percutaneous muscle biopsy samples were obtained, and electrophysiologic examinations were performed during the acute phase and during recovery in patients with acute quadriplegic myopathy. Regulation of muscle contraction and myofibrillar protein synthesis was studied using cell physiologic techniques, ultrasensitive electrophoresis, in situ hybridization, and histopathologic techniques. SETTING: All patients were seen in the intensive care unit of different university hospitals. PATIENTS: All patients were critically ill with sepsis. They had been given massive doses of corticosteroids in combination with variable doses of neuromuscular blocking agents. All patients developed paralysis of spinal nerve-innervated muscles. On the other hand, cranial nerve-innervated muscle and sensory and cognitive functions were well maintained after discontinuation of treatment with neuromuscular blocking agents. INTERVENTION: Muscle biopsy samples were obtained and electrophysiologic examinations were performed in all patients. MEASUREMENTS AND MAIN RESULTS: The major observations in patients with acute quadriplegic myopathy were, as follows: a) a general decrease in myofibrillar protein content; b) specific but highly variable partial or complete loss of myosin and myosin-associated proteins; c) very low thick-filament/thin-filament protein ratios; d) absence of myosin messenger RNA; and e) a dramatically impaired muscle cell force-generating capacity in the acute phase of acute quadriplegic myopathy. During clinical improvement, normal expression of myosin messenger RNAs, reexpression of thick-filament proteins, and increased specific tension were observed. CONCLUSIONS: Acute quadriplegic myopathy is associated with a specific decrease in thick-filament proteins related to an altered transcription rate. Although the decreased content of thick-filament proteins is important for prolonged muscle weakness, it is not the primary cause of muscle paralysis in the acute stage, during which impaired muscle membrane excitability probably plays a more significant role. Several factors contribute to this condition, but the action of corticosteroids seems to be the predominant one, along with potentiation by neuromuscular blocking agents, immobilization, and probably also concurrent sepsis.

Brain dysplasia associated with Larsen-like syndrome.

We present an autopsy case of Larsen-like syndrome with unusually severe neurologic complications. The patient, a 3-year-old girl, manifested severe psychomotor retardation, tetraplegia, and intractable partial seizures as well as multiple joint dislocations with other skeletal deformities, minor external anomalies, and laryngotracheomalacia. Neuropathological examination of the brain revealed (1) cortical dysgenesis in the bilateral perisylvian region; (2) protrusions of the brain parenchyma into the subarachnoid space, (3) abnormal arrangement of olivary neurons, (4) dilation of the lateral ventricles with subventricular gliosis and multiple glial nodules, (5) hypoplasia of the cerebral white matter with subcortical astrocytosis, and (6) necrotic change in Sommer sector of the hippocampus. There were no microscopic abnormalities in the mesenchymal tissue of the brain (i.e., vascular walls and the meninges). Cortical dysgenesis in the perisylvian region was characterized by a zonal heterotopia of pyramidal and granule neurons in the molecular layer, which clinically may be closely related to intractable partial seizures in the orofacial area. Findings 1, 2, and 3 may represent a disturbance of neuroblast migration, speculated to have occurred during the latest stage of migration (around 20-25 weeks gestation). There are few published reports describing the combination of Larsen-like syndrome and brain dysplasia. Correlation of brain dysplasia with congenital skeletal abnormalities is unclear in our patient. We speculate that systemic hypoxic-ischemic insults during the second half of gestation and/or some genetic factors might be possible causes of brain dysplasia.

Monozygotic twin patients with congenital ichthyosis, microcephalus, spastic quadriplegia, myoclonus, and EEG abnormalities.

A pair of monozygotic twins manifested widespread ichthyosis on the trunk and extremities, mainly on the extensor surface of the lower legs. Both patients had severe developmental retardation, microcephalus, spastic quadriplegia, myoclonus, and hearing impairment. Cranial computed tomography and magnetic resonance imaging revealed diffuse cortical atrophy. Electroencephalography documented diffuse slow wave dysrhythmia and marked epileptic discharges, namely bilateral occipital dominant, and low-voltage multifocal spikes which appeared asynchronously as a burst, mainly during sleep. Skin biopsy revealed hyperkeratosis with parakeratosis. Granular cell layer was not thickened and diminished. Papillomatosis was absent. Electron microscopy did not reveal any distinctive abnormalities. Sjögren-Larsson syndrome and other known ichthyosis syndromes were excluded because of the difference in localization of skin lesions, skin manifestations, lack of papillomatosis, the nature and severity of neurologic symptoms and marked electroencephalographic abnormalities.

A familial disorder associated with palatal myoclonus, other brainstem signs, tetraparesis, ataxia and Rosenthal fibre formation.

Three siblings presented with a progressive neurological disorder beginning in the third decade of life and characterised by palatal myoclonus, nystagmus, bulbar weakness and spastic tetraparesis. There was no evidence of intellectual deterioration or seizures. CT scan showed marked brainstem atrophy in two patients and basal ganglia calcification in one. MRI scan in one showed high signal in the brainstem and periventricular region and cerebral biopsy in this patient showed myelin loss and the presence of Rosenthal fibres. A similar disease affected the siblings' mother, maternal aunt and two of the aunt's daughters, suggesting an autosomal dominant mode of transmission of what appears to be a unique genetic disorder.

Familial calcification of the basal ganglia with cerebrospinal fluid pleocytosis.

Two related infants with microcephaly, spastic quadriplegia, and profound retardation are reported. Both showed extensive bilateral symmetrical calcification of the basal ganglia with cerebrospinal fluid pleocytosis.

Sjögren-Larsson syndrome: microscopic and scanning electron microscopic findings in replicas of the skin.

Replicas of the skin below the cubital fossa were made in 29 SLS patients with an age range of 8 days to 69 years. The skin surface patterns differed from those in healthy controls. The papillomatosis observed in most SLS replicas seemed to appear during the first year or years of life and to increase in some patients with increasing age, but seemed to diminish again in middle-aged and older SLS patients. Other common features were the occurrence of longitudinal and transverse furrows. All these findings in SLS patients could, at least in part, represent an exaggeration of the normal skin surface pattern. The use of replicas for diagnostic purposes is commented on.

Hypergonadotropic hypogonadism in oligophrenia.

Eight patients representing five different, probably hereditary neurological syndromes with oligophrenia and hypogonadism as the common features have been examined clinically and endocrinologically. Two sisters suffered from polyneuropathy, one male from ataxia, one male from spastic tetraplegia, two sisters and a brother from myopathy and one male patient from epilepsy and polyneuropathy. The latter patient was diagnosed as having an acute intermittent porphyria. All the patients had degenerative neurological disorders. The karyotypes were normal. The patients all had signs of hypogonadism. Four male patients had marked testicular atrophy but otherwise normal external genitalia. The testosterone levels in the blood were normal or slightly decreased. Three of the females had their menarche at a normal age but a very early menopause. The fourth female has never menstruated. The four females had normal breasts and body hair. All patients had high basal luteinizing hormone (LH) and follicle-stimulating hormone levels and the response to i.v. LH-releasing hormone was exaggerated. The prolactin values were normal. None of the examined patients had any signs of thyroid or adrenal insufficiency and the sella turcica was normal. A possible etiology to their hypergonadotropic hypogonadism is discussed.