A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy.

PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

Biallelic COLGALT1 variants are associated with cerebral small vessel disease.

OBJECTIVE: Approximately 5% of cerebral small vessel diseases are hereditary, which include COL4A1/COL4A2-related disorders. COL4A1/COL4A2 encode type IV collagen α1/2 chains in the basement membranes of cerebral vessels. COL4A1/COL4A2 mutations impair the secretion of collagen to the extracellular matrix, thereby resulting in vessel fragility. The diagnostic yield for COL4A1/COL4A2 variants is around 20 to 30%, suggesting other mutated genes might be associated with this disease. This study aimed to identify novel genes that cause COL4A1/COL4A2-related disorders. METHODS: Whole exome sequencing was performed in 2 families with suspected COL4A1/COL4A2-related disorders. We validated the role of COLGALT1 variants by constructing a 3-dimensional structural model, evaluating collagen ß (1-O) galactosyltransferase 1 (ColGalT1) protein expression and ColGalT activity by Western blotting and collagen galactosyltransferase assays, and performing in vitro RNA interference and rescue experiments. RESULTS: Exome sequencing demonstrated biallelic variants in COLGALT1 encoding ColGalT1, which was involved in the post-translational modification of type IV collagen in 2 unrelated patients: c.452 T > G (p.Leu151Arg) and c.1096delG (p.Glu366Argfs*15) in Patient 1, and c.460G > C (p.Ala154Pro) and c.1129G > C (p.Gly377Arg) in Patient 2. Three-dimensional model analysis suggested that p.Leu151Arg and p.Ala154Pro destabilized protein folding, which impaired enzymatic activity. ColGalT1 protein expression and ColGalT activity in Patient 1 were undetectable. RNA interference studies demonstrated that reduced ColGalT1 altered COL4A1 secretion, and rescue experiments showed that mutant COLGALT1 insufficiently restored COL4A1 production in cells compared with wild type. INTERPRETATION: Biallelic COLGALT1 variants cause cerebral small vessel abnormalities through a common molecular pathogenesis with COL4A1/COL4A2-related disorders. Ann Neurol 2018;84:843-853.

The Persistent Generalized Muscle Contraction in Siblings with Molybdenum Cofactor Deficiency Type A.

Molybdenum cofactor deficiency (MoCD) is a rare autosomal recessive metabolic disease with severe neurological symptoms. Most disease-causing mutations are found in the MOCS1 gene, corresponding to MoCD type A (MoCD-A). There have been few reports describing the long-term detailed neurological features with MoCD-A because most patients do not survive childhood. We describe the clinical, radiologic, biochemical, and genetic data of two patients (female siblings aged 26 and 22 years) with MoCD-A. Both patients presented with feeding difficulties, neurological deterioration, and persistent generalized muscle contraction which can be easily confused with status dystonicus. Biochemical tests revealed low serum uric acid, elevated urinary sulfocysteine, and xanthine. Brain magnetic resonance imaging (MRI) revealed distinctive abnormalities in the bilateral caudate nucleus, putamen, globus pallidus, and cerebral white matter adjacent to the cortex. The thalamus was relatively unaffected. Genetic testing identified a novel homozygous variant in the MOCS1 gene (c.949C > T p.Arg317Cys). Biochemical results supported the hypothesis that this genetic variant is a pathological mutation. When there are symptoms of persistent generalized muscle contraction and characteristic MRI findings, MoCD should be considered as a differential diagnosis.

De novo variants in RHOBTB2, an atypical Rho GTPase gene, cause epileptic encephalopathy.

By whole exome sequencing, we identified three de novo RHOBTB2 variants in three patients with epileptic encephalopathies (EEs). Interestingly, all three patients showed acute encephalopathy (febrile status epilepticus), with magnetic resonance imaging revealing hemisphere swelling or reduced diffusion in various brain regions. RHOBTB2 encodes Rho-related BTB domain-containing protein 2, an atypical Rho GTPase that is a substrate-specific adaptor or itself is a substrate for the Cullin-3 (CUL3)-based ubiquitin ligase complex. Transient expression experiments in Neuro-2a cells revealed that mutant RHOBTB2 was more abundant than wild-type RHOBTB2. Coexpression of CUL3 with RHOBTB2 decreased the level of wild-type RHOBTB2 but not the level of any of the three mutants, indicating impaired CUL3 complex-dependent degradation of the three mutants. These data indicate that RHOBTB2 variants are a rare genetic cause of EEs, in which acute encephalopathy might be a characteristic feature, and that precise regulation of RHOBTB2 levels is essential for normal brain function.

Expanding the phenotype of IBA57 mutations: related leukodystrophy can remain asymptomatic.

Biallelic mutations in IBA57 cause a mitochondrial disorder with a broad phenotypic spectrum that ranges from severe intellectual disability to adolescent-onset spastic paraplegia. Only 21 IBA57 mutations have been reported, therefore the phenotypic spectrum of IBA57-related mitochondrial disease has not yet been fully elucidated. In this study, we performed whole-exome sequencing on a Sepharadi Jewish and Japanese family with leukodystrophy. We identified four novel biallelic variants in IBA57 in the two families: one frameshift insertion and three missense variants. The three missense variants were predicted to be disease-causing by multiple in silico tools. The 29-year-old Sepharadi Jewish male had infantile-onset optic atrophy with clinically asymptomatic leukodystrophy involving periventricular white matter. The 19-year-old younger brother, with the same compound heterozygous IBA57 variants, had a similar clinical course until 7 years of age. However, he then developed a rapidly progressive spastic paraparesis following a febrile illness. A 7-year-old Japanese girl had developmental regression, spastic quadriplegia, and abnormal periventricular white matter signal on brain magnetic resonance imaging performed at 8 months of age. She had febrile convulsions at the age of 18 months and later developed epilepsy. In summary, we have identified four novel IBA57 mutations in two unrelated families. Consequently, we describe a patient with infantile-onset optic atrophy and asymptomatic white matter involvement, thus broadening the phenotypic spectrum of biallelic IBA57 mutations.

Clinical and molecular genetic characterization of two siblings with trisomy 2p24.3-pter and monosomy 5p14.3-pter.

Partial trisomy 2p syndrome is occasionally associated with neural tube defects (NTDs), such as anencephaly, encephalocele, and spina bifida, in addition to common features of intellectual disability, developmental delay, and characteristic facial appearance. The 2p24 region has been reported to be associated with NTDs. Here, we report the cases of 2 siblings with trisomy 2p24.3-pter and monosomy 5p14.3-pter caused by the paternal translocation t(2;5)(p24.3;p14.3). Of the two siblings, the elder sister had spina bifida. We determined the nucleotide sequences of the chromosomal breakpoints and found that the sizes of trisomy 2p and monosomy 5p segments were 18.77 and 17.89 Mb, respectively. NTDs were present in four of seven previously reported patients with trisomy 2p and monosomy 5p as well as in one of the two patients examined in the present study. Although the monosomy 5p of the nine patients were similar in size, the two patients reported here had the smallest size of trisomy 2p. When the clinical features of the nine patients were compared to the present two patients, the elder sister had postaxial polydactyly of the left foot in addition to the characteristic facial appearance and spina bifida, indicating that these features were associated with trisomy 2p24.3-pter. To our knowledge, this is the first study on spina bifida to determine the nucleotide sequences of breakpoints for trisomy 2p24.3-pter and monosomy 5p14.3-pter. Increased gene dosages of dosage-sensitive genes or genes at the trisomy segment (2p24.3) of the presented patients could be associated with NTDs of patients with trisomy 2p.

A case report of mitochondrial respiratory chain disorder in the neonatal period for which home mechanical ventilation was introduced.

We report the case of a patient born with extreme muscle hypotonia, respiratory failure, and slightly elevated serum levels of lactic acid. Histochemical examination and mitochondrial respiratory chain enzyme activities of a muscle biopsy specimen revealed reduced activities of complexes Ⅰ, Ⅲ, and Ⅳ, diagnostic of mitochondrial respiratory chain disorder. Hypertrophic cardiomyopathy developed as a complication and additional therapy was administered at 3 months after birth. He was able to be discharged to home on applied home mechanical ventilation with tracheotomy at 1 year old. The patient survived until 4 years and 10 months of age, upon which he died of bronchitis. Early-onset mitochondrial respiratory chain disorder shows very poor prognosis and long-term survival has not been reported. Prompt assessment of mitochondrial respiratory chain enzyme activities is necessary for the diagnosis of congenital nonspecific multiple-organ failure, and early intervention may achieve better prognosis for mitochondrial respiratory chain disorder.

Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion.

BACKGROUND: Short-chain enoyl-CoA hydratase-ECHS1-catalyses many metabolic pathways, including mitochondrial short-chain fatty acid ß-oxidation and branched-chain amino acid catabolic pathways; however, the metabolic products essential for the diagnosis of ECHS1 deficiency have not yet been determined. The objective of this report is to characterise ECHS1 and a mild form of its deficiency biochemically, and to determine the candidate metabolic product that can be efficiently used for neonatal diagnosis. METHODS: We conducted a detailed clinical, molecular genetics, biochemical and metabolic analysis of sibling patients with ECHS1 deficiency. Moreover, we purified human ECHS1, and determined the substrate specificity of ECHS1 for five substrates via different metabolic pathways. RESULTS: Human ECHS1 catalyses the hydration of five substrates via different metabolic pathways, with the highest specificity for crotonyl-CoA and the lowest specificity for tiglyl-CoA. The patients had relatively high (∼7%) residual ECHS1 enzyme activity for crotonyl-CoA and methacrylyl-CoA caused by the compound heterozygous mutations (c.176A>G, (p.N59S) and c.413C>T, (p.A138V)) with normal mitochondrial complex I-IV activities. Affected patients excrete large amounts of N-acetyl-S-(2-carboxypropyl)cysteine, a metabolite of methacrylyl-CoA. CONCLUSIONS: Laboratory data and clinical features demonstrated that the patients have a mild form of ECHS1 deficiency harbouring defective valine catabolic and ß-oxidation pathways. N-Acetyl-S-(2-carboxypropyl) cysteine level was markedly high in the urine of the patients, and therefore, N-acetyl-S-(2-carboxypropyl)cysteine was regarded as a candidate metabolite for the diagnosis of ECHS1 deficiency. This metabolite is not part of current routine metabolic screening protocols, and its inclusion, therefore, holds immense potential in accurate diagnosis.

De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly.

Porencephaly is a neurological disorder characterized by fluid-filled cysts or cavities in the brain that often cause hemiplegia. It has been suggested that porencephalic cavities result from focal cerebral degeneration involving hemorrhages. De novo or inherited heterozygous mutations in COL4A1, which encodes the type IV α1 collagen chain that is essential for structural integrity for vascular basement membranes, have been reported in individuals with porencephaly. Most mutations occurred at conserved Gly residues in the Gly-Xaa-Yaa repeats of the triple-helical domain, leading to alterations of the α1α1α2 heterotrimers. Here we report on two individuals with porencephaly caused by a heterozygous missense mutation in COL4A2, which encodes the type IV α2 collagen chain. Mutations c.3455G>A and c.3110G>A, one in each of the individuals, cause Gly residues in the Gly-Xaa-Yaa repeat to be substituted as p.Gly1152Asp and p.Gly1037Glu, respectively, probably resulting in alterations of the α1α1α2 heterotrimers. The c.3455G>A mutation was found in the proband's mother, who showed very mild monoparesis of the left upper extremity, and the maternal elder uncle, who had congenital hemiplegia. The maternal grandfather harboring the mutation is asymptomatic. The c.3110G>A mutation occurred de novo. Our study confirmed that abnormalities of the α1α1α2 heterotrimers of type IV collagen cause porencephaly and stresses the importance of screening for COL4A2 as well as for COL4A1.

Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly.

OBJECTIVE: Recently, COL4A1 mutations have been reported in porencephaly and other cerebral vascular diseases, often associated with ocular, renal, and muscular features. In this study, we aimed to clarify the phenotypic spectrum and incidence of COL4A1 mutations. METHODS: We screened for COL4A1 mutations in 61 patients with porencephaly and 10 patients with schizencephaly, which may be similarly caused by disturbed vascular supply leading to cerebral degeneration, but can be distinguished depending on time of insult. RESULTS: COL4A1 mutations were identified in 15 patients (21%, 10 mutations in porencephaly and 5 mutations in schizencephaly), who showed a variety of associated findings, including intracranial calcification, focal cortical dysplasia, pontocerebellar atrophy, ocular abnormalities, myopathy, elevated serum creatine kinase levels, and hemolytic anemia. Mutations include 10 missense, a nonsense, a frameshift, and 3 splice site mutations. Five mutations were confirmed as de novo events. One mutation was cosegregated with familial porencephaly, and 2 mutations were inherited from asymptomatic parents. Aberrant splicing was demonstrated by reverse transcriptase polymerase chain reaction analyses in 2 patients with splice site mutations. INTERPRETATION: Our study first confirmed that COL4A1 mutations are associated with schizencephaly and hemolytic anemia. Based on the finding that COL4A1 mutations were frequent in patients with porencephaly and schizencephaly, genetic testing for COL4A1 should be considered for children with these conditions.

The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations.

Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.

[Cervical myelopathy associated with os odontoideum after botulinum toxin treatment in a patient with cerebral palsy].

Os odontoideum is a separate ossicle from the odontoid process from the body of the axis by a variable transverse gap. A boy with cerebral palsy probably due to prematurity and kernicterus, was treated with botulinum toxin for continuous dystonic movements at the age of 3.5 years. Although botulinum toxin appeared to be remarkably effective for relaxing hypertonia, abnormal frequent anterior flexion of the neck remained. Because of feeding difficulty and frequent aspiration episodes, additional botulinum toxin therapy was discontinued. His condition seemed to be stable and he could walk with support at age 7. However, at age 8, he presented with decreased movement of the extremities and bilateral ankle clonus. Radiographic examination of the cervical spine revealed cystic lesion and os odontoideum. With cervical posterior fixation, the patient made a good recovery. Although athetoid cerebral palsy displays an increased risk of cervical myelopathy, os odontoideum is rare in early childhood. The frequent dynamic stress of the neck due to an unbalanced, persistently contracted state and sudden collapse, possibly attributed to botulinum toxin therapy, might have led to atlantoaxial instability and os odontoideum.

[Clinical profile of persistent generalized muscle contraction following the insult of developing brain].

OBJECTIVE: Persons with severe motor and intellectual disabilities (SMID) caused by injury to the developing brain sometimes present generalized hypertonia in a specific position with extreme muscle overactivity persisting for most of the time during wakefulness. This "persistent generalized muscle contraction" is often associated with bad humor, sleep disturbance, hyperhidrosis, wasting, elevation of serum creatine kinase levels, regular daytime use of hypnotic or sedative medication, and the necessity to maintain the neck or hip in a flexed position manually. The aim of this study is to elucidate the clinical profile of this condition. METHODS: We retrospectively examined the medical records and brain imaging data of 66 SMID patients in the state of persistent generalized muscle contraction. RESULTS: Most patients could be classified into 2 major categories on the basis of clinical presentation and brain imaging: (A) those with premature birth and bilateral lesion of globus pallidus interna (kernicterus) (n = 16), and (B) those with various widespread bilateral basal ganglia/thalamic and/or cerebral lesions such as hypoxia-ischemia, acute encephalopathy, malformation, etc (n = 50). Group A assumed an asymmetrical tonic-neck-reflex-like position, torsion of the trunk, fluctuation of hypertonia, and better mental development. Three of them exhibited extreme hypertonia resembling status dystonicus. Group B often exhibited persistent and fixed retroflexion of the neck and trunk or opisthotonus. Drugs such as oral muscular relaxants were ineffective in both groups. Injection of botulinum toxin into the cervical and paravertebral muscles partially alleviated symptoms. CONCLUSIONS: Persistent generalized muscle contraction in SMID has at least two different types. Group A has characteristics of severe dystonic hypertonia that could lead to status dystonicus. Group B might have peculiar characteristics of muscle overactivity triggered by wakefulness or discomfort, which probably results from inability to achieve spontaneous muscle relaxation.

Two concurrent chromosomal aberrations involving interstitial deletion in 1q24.2q25.2 and inverted duplication and deletion in 10q26 in a patient with stroke associated with antithrombin deficiency and a patent foramen ovale.

Advanced high-throughput molecular cytogenetic analysis has enabled the identification of small chromosomal rearrangements, and two or more concurrently occurring chromosomal rearrangements have been identified using this technique. A girl with severe psychomotor developmental delay associated with an uncertain abnormality (detected by conventional karyotyping) in chromosome 10q had a sudden stroke at the age of 35 months. Laboratory and radiographic examinations revealed antithrombin (AT) deficiency and a patent foramen ovale (PFO). Two concurrent chromosomal aberrations, inverted duplication and deletion in the 10q26 region and a microdeletion in the 1q24.2q25.2 region including the AT gene (SERPINC1), were identified by microarray-based comparative genomic hybridization analysis. Both chromosomal aberrations were found to be of paternal origin. This study described the concurrence of chromosomal rearrangements involving two chromosomes, and estimated the frequency of two or more chromosomal aberrations as 2-4%.

A case of ATR-X syndrome with mitochondrial respiratory chain dysfunction.

Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by a mutation in ATRX, which is essential for proper chromatin remodeling. ATRX dysfunction leads to dysregulation of many genes due to abnormal chromatin remodeling, and causes a multisystem disorder in patients with ATR-X. Because mitochondrial disorders also show multisystem involvement, whether mitochondrial function is affected in patients with ATR-X is of interest. Here, we report a case of a 4-year-old male with a mutation (NM_000489.4: c.736C > T p.Arg246Cys) in ATRX, who showed mitochondrial dysfunction with complex I deficiency. The results from our study suggest that target genes of the ATRX protein may include those responsible for mitochondrial function, and mitochondrial dysfunction may contribute to some ATR-X phenotypes.

Dietary chloride deficiency due to new liquid nutritional products.

BACKGROUND: In infants the ingestion of chloride-deficient formulas was previously reported to cause hypochloremic metabolic alkalosis and hypokalemia, which is referred to as dietary chloride deficiency syndrome. Since that time, however, dietary chloride deficiency has not been commonly recognized. The aim of the present study was to evaluate the clinical features of dietary chloride deficiency syndrome caused by the ingestion of newly marketed liquid nutritional products. METHODS: This was a retrospective chart review of 59 patients with severe motor and intellectual disability (SMID); they had been given newly marketed liquid nutritional products that were later found to be chloride deficient. RESULTS: Eight-nine weeks after changing to the new liquid nutritional products, clinical symptoms and laboratory abnormalities were noted. The main clinical finding was weight loss; 22% of subjects lost >5% of their bodyweight. A small number of the subjects had a mild bowel movement disorder; diarrhea and constipation were found in six and three patients, respectively. Hyponatremia, hypokalemia, and hypochloremia occurred in 33.9%, 44.5%, and 50.8%, respectively. CONCLUSIONS: Chloride-deficient liquid nutritional products can cause weight loss, hypochloremic metabolic alkalosis, and hypokalemia in persons with severe motor and intellectual disability.

Neonatal MRI in preterm infants with periventricular leukomalacia and mild disability.

BACKGROUND: The aim of the present study was to describe the neonatal magnetic resonance imaging (MRI) findings of preterm infants with periventricular leukomalacia and mild neurological disability. METHODS: MRI findings at term equivalent were retrospectively investigated in eight preterm infants with mild disability and periventricular leukomalacia diagnosed on MRI in infancy. RESULTS: Linear, spotted, or macular areas of hyperintensity on T1-weighted imaging and hypointensity on T2-weighted imaging were identified in all subjects in the white matter lateral to the body of the lateral ventricle. No cystic lesions were seen. These findings were more widespread and more clearly visualized on T2-weighted imaging than T1-weighted imaging. CONCLUSIONS: Linear, spotted, or macular lesions that are hyperintense on T1-weighted imaging and hypointense on T2-weighted imaging are possibly compatible with periventricular leukomalacia.

[Cerebral palsy].

Great advances have been made in the causes, lesions and symptoms of cerebral palsy over the years. Children with athetosis have lesions of the ventral lateral nuclei of the thalamus and putamen. Cocontraction and overflow are considered essential problems in athetosis. Some patients with a lesion of the ventral lateral nucleus of the thalamus do not show any involuntary movements. Children with periventricular leukomalacia demonstrate various patterns of the hip, knee and ankle in response to bearing body weight. Some of these patients exhibit ataxia, tremor and mouth opening triggered by voluntary movements. They have various central visual disorders or visual cognitive disorders. They also exhibit paroxysmal ocular downward deviation. In early infancy with spastic diplegia, there is no isolated extension of the knee or leg elevation. Hemiplegia results from stroke of the middle cerebral artery or venous infarction during the fetal or neonatal period. Border-zone infarction results from partial asphyxia.