Infantile Bilateral Striatal Necrosis Research Articles

NUP62 is required for the maintenance of the spindle assembly checkpoint and chromosomal stability.

The nuclear pore protein NUP62 localizes to spindle poles in mitosis and plays a role in maintaining centrosome homeostasis. In this study, we found that NUP62-depleted cells exhibited a defective spindle assembly checkpoint (SAC) and that depletion of NUP62 caused a slight decrease in MAD2 protein levels after nocodazole treatment. However, depletion of NUP62 did not cause a failure in kinetochore localization of the SAC proteins BUBR1, MAD1, and MAD2 in prometaphase. NUP62 depletion slightly prolonged mitotic timing but did not affect cell doubling time. In addition, NUP62 depletion caused a SAC defect and induced aneuploidy in human neural stem cells. Furthermore, overexpression of NUP62Q391P, a mutant protein causing autosomal recessive infantile bilateral striatal necrosis, resulted in a defect in the SAC, indicating that the amino acid residue Q391 in NUP62 is crucial for its effect on the SAC. Overall, we conclude that NUP62 maintains the SAC downstream of kinetochores and thereby ensures maintenance of chromosomal stability.

Cytokine Production by Mononuclear Cells from Patients with Familial Infantile Bilateral Striatal Necrosis

Prompted by findings suggesting immune instability in infantile bilateral striatal necrosis (IBSN), we evaluated levels of proinflammatory (tumor necrosis factor α, interleukin [IL]-1β, IL-6, interferon [IFN]γ) and anti-inflammatory (IL-10 and IL-1ra) cytokines produced by peripheral blood mononuclear cells (PBMC) from 6 children with IBSN and 11 age-matched controls. Compared to controls, non-stimulated PBMC from the IBSN group produced a significantly lower level of IL-1ra (by 38%; p < 0.001) and significantly lower levels of TNFα, IL-1β, and IFNγ (by 36% [p < 0.001], 25% [p = 0.06], and 32% [p < 0.02]) under PBMC stimulation. The severe cachexia manifesting shortly after IBSN onset may impair the immunological state, placing patients at risk of death from hyperpyrexia and sepsis.

Targeted next generation sequencing in patients with infantile bilateral striatal necrosis

Background: Infantile bilateral striatal necrosis (IBSN) is a heterogeneous histo- pathologically condition defined by the involvement of the neostriata that can be observed in a very large number of neurological conditions clinically dominated by the presence of movement disorders. Methods: In a prospective study over the course of 1 year, we applied targeted next generation sequencing (NGS) of 78 genes linked to IBSN, using Sure Design Tool from Agilent Technologies. In addition, we studied biomarkers of known causes of IBSN, including blood interferon signature and free-thiamine and pterins in CSF. Results: We included 21 patients (16 male, age 1 month to 8 years; media ± SD 2.1 ± 1.6). Onset of symptoms was acute in almost all patients. Interferon signature was altered in two patients with Aicardi-Goutierès syndrome. Low free thiamine and elevated pterins in CSF were detected in 2 and 3 patients, respectively. T2-hyperintensities in other regions besides the neostriata were observed in 3/21 patients. We established firm molecular diagnosis in about 38% (8/21) of patients, with mutations been identified in the following genes: RNASEH2B, IFIH1, PDH1A, ADAR, SLC25A19 and NDUFAF6 (3 patients), including two novel mutations in SLC25A19 (c.580T>C) and ADAR (c.2187_2198delTGGCCTTTTGGAinsGT). We presented here the second reported pedigree of mutation in SLC25A19. The mutation is different as that found in the only other described family with SLC25A19 deficiency. Discussion: Targeted NGS leads to rapid and cost-effective detection of causative mutations in IBSN. We have reached a diagnostic rate similar to that described in the literature. Our study expands the very few descriptions of patients with SLC25A19 mutation.

Cerebrospinal Fluid Monoamine Metabolite Analysis in Pediatric Movement Disorders.

Abnormal concentrations of dopamine and serotonin metabolites in the cerebrospinal fluid is the diagnostic hallmark of a group of treatable conditions known as the monoamine neurotransmitter disorders. We assessed cerebrospinal fluid dopamine and serotonin metabolite concentrations in a series of 69 patients affected by movement disorders of unknown etiology. Abnormal results were disclosed in 13/69 subjects (19%). Both primary and secondary monoamine neurotransmitter disorders were observed. The clinical presentation of both forms was hypokinetic-rigid syndrome or dystonia. L-Dopa treatment resulted in significant improvement of the clinical picture in the majority of primary neurotransmitter disorders. Eight patients presented a secondary neurotransmitter disorder. One suffered from a GM2 gangliosidosis and one from infantile bilateral striatal necrosis. Etiologic diagnoses were not established in the others. L-Dopa was started in four patients, leading to a significant improvement of hypokinesia in the patient suffering from GM2 gangliosidosis and a slight improvement in 3 unclassified patients.

Homozygous missense mutation of NDUFV1 as the cause of infantile bilateral striatal necrosis

Infantile bilateral striatal necrosis (IBSN) includes a heterogeneous group of disorders, characterized by symmetrical degeneration predominantly of the caudate nucleus and the putamen [1]. The clinical features encompass pyramidal and extrapyramidal signs such as choreoathetosis, dystonia, spasticity, dysarthria, and dysphagia in conjunction with developmental regression or mental retardation, and additional neurological symptoms [1]. The differential diagnosis has to take into account a variety of toxic, infectious, metabolic, and neurodegenerative disorders [1]. In familial cases, mutations in the mitochondrial genes ATP6 and ND6, and in the nuclear encoded genes nucleoporin 62 (NUP62) and mitochondrial thiamine pyrophosphate transporter (SLC25A19), have been described [2]. We report two siblings with IBSN and a mutation in NDUFV1, not yet linked to this condition. The patients’ parents are unrelated, but belong to a population of German settlers immigrating to Russia about 250 years ago (Fig. 1c). In both children, gait and speech difficulties were noticed from age 4 years. Neurological examination at age 9 (F3) and 5 years (F5) revealed dysarthria, muscular hypertonia with cogwheel rigidity, exaggerated deep tendon reflexes, and bilateral Babinski signs, while MRI demonstrated symmetric cystic lesions of the putamen (Fig. 1a, b). The patients were treated with biotin and thiamine before the definite diagnosis was established, and additionally, with creatine, riboflavin, and other vitamins thereafter. This resulted in a distinct and sustained improvement of their neurological status until last examination at age 11 and 7 years, respectively. Both still walk and attend regular schools. Biochemical analysis of a muscle biopsy from patient F3 revealed isolated complex I deficiency (0.08 U/U citrate synthetase; normal 0.17–0.56). Therefore, we sequenced the entire mtDNA including the genes ATP6 and ND6 without detecting pathogenic variants [3, 4].

P21.7 Biotin non-responsive familial infantile bilateral striatal necrosis associated with primary influenzae A infection

P21.7 Biotin non-responsive familial infantile bilateral striatal necrosis associated with primary influenzae A infection

Acute Infantile Bilateral Striatal Necrosis: Single-Photon Emission Computed Tomography (SPECT) Imaging and Review

Acute infantile bilateral striatal necrosis is a rarely described acute neurological syndrome associated with radiological findings. Its etiology and pathogenic mechanisms are unknown. Clinically, the syndrome usually follows respiratory illnesses and presents with an array of neurological findings, including axial ataxia, grimacing, mutism, head nodding, and high-pitched cry. This study follows a child with acute infantile bilateral striatal necrosis both clinically and radiologically. In addition, for the first time, the authors describe the serial findings of single-photon emission computed tomography (SPECT) from onset of illness through 20 months. Their findings indicate an initial insult apparent on both magnetic resonance imaging and SPECT localized to the basal ganglia, which, although improved over time, does not fully regress. The residual lesion on SPECT was clinically associated with only mild attention deficit disorder and no motor pathology. The authors review the published literature concerning acute infantile bilateral striatal necrosis and suggest possible mechanisms of this poorly understood and probably underreported condition.

Genetics of Infantile Bilateral Striatal Necrosis

The gene mutation causing autosomal recessive infantile bilateral striatal necrosis (IBSN) was identified in eight consanguineous Israeli Bedouin families, in a study at Schneider Children’s Medical Center, Petah Tikva, Israel, and other centers.

Infantile bilateral striatal necrosis associated with human herpes virus-6 (HHV-6) infection

A 1-year-old female with acute bilateral striatal necrosis secondary to exanthema subitum associated with human herpesvirus 6 (HHV-6) infection is reported. The patient was previously healthy. She presented with progressive neurologic signs of oral dyskinesia and involuntary movements, after suffering from exanthema subitum. Initial magnetic resonance imaging (MRI) demonstrated abnormal signals in the bilateral striatal regions. In addition, the serum HHV-6 IgM class antibody level was significantly increased. The patient is thought to be the first case of HHV-6 infection related infantile bilateral striatal necrosis (IBSN).

Infantile bilateral striatal necrosis maps to chromosome 19q.

Infantile bilateral striatal necrosis (IBSN) encompasses several syndromes of bilateral symmetric degeneration of the caudate nucleus, putamen, and globus pallidus. Autosomal recessive IBSN is characterized clinically by developmental arrest beginning at age 7 to 15 months, dysphagia, choreoathetosis, pendular nystagmus and optic atrophy, and severe progressive atrophy of the basal ganglia on MRI. To map the gene causing IBSN. A 10-cM genome-wide linkage scan was initially performed on five affected and five unaffected individuals. The extended family was included in the analysis to narrow the candidate region. Logarithm of odds (LOD) score was calculated using the SUPERLINK program. Linkage to the chromosomal region 19q13.32-13.41 was established (Z(max) = 6.27 at theta = 0.02 at locus D19S412). Recombination events and a common disease-bearing haplotype defined a critical region of 1.2 Mb between the loci D19S596 proximally and D19S867 distally. IBSN maps to the chromosomal region 19q13.32-13.41. The presence of a common haplotype in all the patients suggests that the disease is caused by a single mutation derived from a single ancestral founder in all the families.

Familial Infantile Bilateral Striatal Necrosis

The clinical and radiological evolution of familial infantile bilateral striatal necrosis (IBSN) was evaluated in 11 of 15 affected children born to consanguineous Israeli Bedouin parents and reported from the Schneider Children’s Medical Center, Petah Tikva and Sackler School of Medicine, Tel Aviv University, and other centers in Israel.

Post-streptococcal autoimmune dystonia with isolated bilateral striatal necrosis.

Infantile bilateral striatal necrosis (IBSN) is characterized by a dystonic movement disorder and basal ganglia imaging abnormalities. Acute IBSN often occurs after upper respiratory tract infections although no specific micro-organism which may cause IBSN has been identified. We present 2 children (1 year 2 months and 4 years) with acute IBSN after clinical pharyngitis. Both IBSN patients had serological evidence of recent beta-haemolytic streptococcal infection. Due to the association of post-streptococcal disorders with anti-basal ganglia antibodies (ABGA), we examined both patients for anti-neuronal antibodies. For comparison, 20 children with dystonia (9 females, 11 males; mean age 4 years 1 month), and 20 children with uncomplicated streptococcal infection (12 females, 8 males; mean age 5 years 9 months) were examined. Both IBSN patients had antibodies reactive against basal ganglia constituents of molecular weight 40 kDa. Immunohistochemistry showed antibody reactivity against large striatal neurons only. Other anti-neuronal antibodies were negative, supporting striatal specificity. All controls were negative for ABGA. Acute IBSN is part of the poststreptococcal autoimmune neuropsychiatric spectrum. An autoimmune aetiology should be considered in this phenotype, as immunomodulatory therapies may reduce morbidity and mortality.

Serial MRI in infantile bilateral striatal necrosis

A 3-year-old girl with left hemiparesis suffered from bilateral paresis, motor rigidity, gait disturbance, axial hypotonia, dysarthria, apathy, and incontinence. After steroid therapy, mild improvement occurred, but muscle weakness, gait disturbance, and rigidity remained. Leigh encephalopathy was excluded on the basis of muscle biopsy and laboratory findings. Computed tomography and serial magnetic resonance imaging at an early stage revealed right-sided dominant lesions in the putamen and caudate nucleus and later bilateral striatal lesions, appearing as hyperintense signals on T 2-weighted images and mixtures of hypo- and hyperintense signals on T 1-weighted images. This is the first demonstration of serial magnetic resonance imaging findings in infantile bilateral striatal necrosis.

Infantile bilateral striatal necrosis: chronic and acute manifestations in a single case

We report a girl who exhibited a slowly progressive extrapyramidal disorder with onset in early infancy. CT examinations demonstrated progressive atrophy of the cerebrum. At the age of 6 years, acute exacerbation occurred with impairment of consciousness and automomic functions. During the acute episode, CT revealed lesions in the bilateral striatum and globus pallidus.

Acute neurologic dysfunction associated with destructive lesions of the basal ganglia: A benign form of infantile bilateral striatal necrosis

In 1982 Gouti6res and Aicardi ~ described three patients with a syndrome characterized by (1) an abrupt clinical onset after an infectious illness, (2) impaired consciousness, axial hypotonia, motor rigidity, and abnormal movements and postures, (3) sustained improvement of neurologic status, and (4) bilateral low-density lesions of the basal ganglia on the computed tomographie scan. Three similar patients also have been repor ted) 4 It is likely that some other patients described before the advent of modern neuroimaging techniques had this same syndrome) Huntington chorea, Wilson disease, Hallervorden-Spatz syndrome, mitochondrial eneephalomyopathies including Leigh syndrome, familial striatal necrosis, head trauma, hypoxia-ischemia, and various intoxications can occur in childhood with acute or subaeute neurologie dysfunction associated with bilateral low-density lesions in the basal ganglia. The outcome of all of them, however, is poorer than that of acute neurologic dysfunction associated with destructive lesions of the basal ganglia, as described by Gouti6res and Aicardi. 1 We describe two patients with A D B G who had a complete clinical recovery. The CT scan findings in the acute phase of the disease were identical in both patients and supported the diagnosis. Bilateral, symmetric, necrotic lesions of the basal ganglia were found in the magnetic resonance imaging studies from the early stages of the disease and persisted in our second patient up to 5 years later.

Defect in succinate oxidation by isolated muscle mitochondria in a patient with symmetrical lesions in the basal ganglia

A 3-year-old boy was referred for evaluation of psychomotor retardation. He had a waddling gait with proximal hypotonia and paresis. Computed tomography (CT scan) and magnetic resonance imaging (MRI) of the brain demonstrated symmetrical lesions in the basal ganglia suggesting bilateral necrosis. Lactate and pyruvate levels in blood and cerebrospinal fluid were persistently elevated. A biopsy of the quadriceps muscle showed normal light microscopic findings except for a slightly raised number of lipid droplets. Electron microscopy confirmed this and also showed a rather large number of subsarcolemmal mitochondria without crystalline inclusions. Biochemical studies showed a normal carnitine level and normal mitochondrial enzyme activities in muscle homogenate, including succinate-cytochrome c reductase. However, intact isolated mitochondria failed to oxidize succinate. An explanation for this paradoxical finding is a deficiency in that part of the coenzyme Q (CoQ) that is reduced by the succinate dehydrogenase complex. The differential diagnosis between Leigh's syndrome and infantile bilateral striatal necrosis (IBSN) is discussed. The role of neuroradiology in prompting complementary investigations is stressed.