Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.

Late-onset nonketotic hyperglycinemia with a heterozygous novel point mutation of the GLDC gene.

BACKGROUND: Atypical nonketotic hyperglycinemia is characterized by heterogeneous phenotypes that often include nonspecific behavioral problems, cognitive deficits, and developmental delays. PATIENT: We describe a girl with late-onset nonketotic hyperglycinemia presenting at 5 years of age with hypotonia, chorea, ataxia, and alterations in consciousness in the setting of febrile illness. RESULTS: Serum amino acid analysis was mildly elevated; however, urine amino acid analysis was instrumental in demonstrating marked hyperglycinuria. Mutation testing showed a heterozygous novel sequence change/point mutation in the glycine decarboxylase gene. CONCLUSIONS: This patient illustrates the importance of obtaining urine amino acids in individuals whose clinical manifestations are suspicious for any form of nonketotic hyperglycinemia, because this testing may provide more prominent evidence of elevations in glycine. She also illustrates the potential for a heterozygous mutation to result in manifestations of an atypical form of nonketotic hyperglycinemia.

White matter changes in an untreated, newly diagnosed case of classical homocystinuria.

The authors report the case of a 4-year-old boy who developed progressive unilateral weakness and developmental delays prior to his diagnosis of classical homocystinuria. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse white matter changes, raising the concern for a secondary diagnosis causing leukoencephalopathy, since classical homocystinuria is not typically associated with these changes. Other inborn errors of the transsulfuration pathway have been reported as causing these changes. Once begun on therapy for his homocystinuria, his neurologic deficits resolved and his delays rapidly improved. Repeat MRI performed one year after instating therapy showed resolution of his white matter abnormalities. This case illustrates the need to consider homocystinuria and other amino acidopathies in the differential diagnosis of childhood white matter diseases and lends weight to the hypothesis that hypermethioninemia may induce white matter changes.

Human arboviral encephalitis.

Worldwide, arboviral illnesses constitute the most important international infectious threat to human neurological health and welfare. Before the availability of effective immunizations, approximately 50,000 cases of Japanese encephalitis occurred in the world each year, one-fifth of which cases proved lethal and a much larger number were left with severe neurological handicaps. With global climate change and perhaps other factors, the prevalences of some arboviral illnesses appear to be increasing. Arboviral illnesses, including Japanese encephalitis, tick-borne encephalitis, Yellow fever, and others, are emerging as possible global health care threats because of biological warfare. This chapter will review ecology, pathophysiology, diagnosis, management, and outcome of the forms of arboviral encephalitis that are of greatest importance in North America, together with some of the most important arboviral encephalitides prevalent in other parts of the world.

An unusual presentation of anti-Hu-associated paraneoplastic limbic encephalitis.

Paraneoplastic limbic encephalitis is a rare disorder characterized by personality changes, seizures, memory loss, and psychiatric symptoms often associated with antineuronal antibodies. It is well described in the adult literature but is still underreported in the pediatric literature. Symptoms are usually multifocal and subacute in presentation, occurring over days to weeks; however, in rare cases, symptom onset can be more gradual. We report the case of a 9-year-old male with anti-Hu-associated paraneoplastic limbic encephalitis that presented as episodic ataxia and behavioral changes evolving to intractable epilepsy and worsening behavioral changes over the course of a year. This case highlights the importance of considering a paraneoplastic disorder in the differential diagnosis for unexplained multifocal neurological symptoms of subacute or chronic onset as earlier detection and treatment may result in an improved outcome.

What the child neurologist should know at the conclusion of training: history taking, examination, and formulation (and a few other generalizations).

Taking of neurological history, performance of neurological examination, and the employment of these sets of information to properly formulate a neurological question constitute the most fundamantal skills of the neurologist. Intelligent facility with these skills must be required of every child neurologist at the completion of training. They will subsequently be refined upon the basis of experience and wider knowledge of neurology and neuroscience which will improve upon the initial level of facility. There are other habits of mind and approach that must also be expected to have been awakened and refined by the time that formal training has been completed.

What the child neurologist should know about neurocutaneous conditions.

At the completion of the general phase of neurological training, the child neurologist cannot be expected to have at the fingertips a comprehensive knowledge of the broad field and complex field of neurocutaneous disorders. The curiosity to seek out neurocutaneous features, especially where they may be relevant to a problem upon which a patient or family is consulting, is to be expected. So is acquaintance with clinical findings and neurological manifestations of certain conditions that assume particular importance because of they are particularly prevlaent or particularly serious.

What the child neurologist should know about the visual system.

The visual system provides an important and highly sensitive opportunity to localize and diagnose neurological diseases. Within the context of the enormous sybject of neuro-ophthalmology there are fundamentals that should be known at the completion of training by the child neurologist. Upon the basis of this information the child neurologist may increase and refine sophistication through the course of an ensuing career.

Extrapontine myelinolysis resulting in transient cortical blindness.

Central pontine myelinolysis and extrapontine myelinolysis are characterized by symmetric demyelination subsequent to rapid shifts in serum osmolality. Described here is a novel case of transient cortical blindness in association with imaging features of extrapontine myelinolysis, which occurred in a child with carbamoyl phosphate synthetase deficiency after rapid correction of hyperammonemia. Serum sodium levels were within normal limits at presentation and throughout the period of ammonia correction. A potential pathogenic mechanism of osmotic demyelination in the setting of acute treatment for hyperammonemia in a patient with a urea cycle abnormality includes disruption of the blood-brain barrier and re-equilibration of organic osmolytes, particularly glutamine.

Outcomes in treatment of infantile spasms with pulse methylprednisolone.

The authors report their experience with intravenous methylprednisolone for the treatment of infantile spasms. A pulse dose of 20 mg/kg intravenous methylprednisolone on each of 3 successive days, followed by a 2-month oral prednisolone taper, led to the rapid remission (range, 2-6 days) of infantile spasms in 5 of 10 (50%) infants. In the subgroup of infants treated within 1 month of onset, 5 of 6 (83%) experienced remission within 6 days. The authors estimate the medication cost of intravenous methylprednisolone with prednisolone taper to be less than $200. In comparison, the cost of a typical course of adrenocorticotropic hormone in the United States can exceed $70,000. Initial treatment with intravenous methylprednisolone and/or oral corticosteroids is a reasonable cost-effective approach to infantile spasms. The lack of serious side effects, low cost, availability, ease of administration, and comparable efficacy suggests that intravenous methylprednisolone merits consideration for study in randomized prospective trials.