Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis

OBJECTIVE: The objective of this study was to identify the gene causing autosomal recessive infantile bilateral striatal necrosis. METHODS: We have mapped the disease gene in the candidate region to approximately 230kb on 19q13.33 in 8 interrelated families including a total of 12 patients and 39 unaffected individuals. RESULTS: Sequencing of the nup62 gene showed a missense mutation causing a change from glutamine to proline (Q391P) in all the patients, producing a substitution from a polar, hydrophilic residue to a nonpolar, neutral residue. All the other 12 candidate genes were sequenced, and no pathogenic sequence changes were found. Comparisons of p62 protein sequences from diverse species indicate that glutamine at position 391 is highly conserved. Five prenatal diagnoses were performed in three at-risk families. INTERPRETATION: This is the second example of a nuclear pore complex protein causing mendelian disease in humans (the first one is triple A syndrome). Our findings suggest that p62 has a cell type-specific role and is important in the degeneration of the basal ganglia in humans.     

Familial holotopistic striatal necrosis

Summary Five cases of a rare neurological disorder occurring in two families are described. Clinically these cases showed: 1. onset in childhood, 2. no known history of episodes of anoxia or intoxication, 3. awkward gait, 4. stiffness or flaccidity of the limbs, athetotic movements and Foerster's signs, 5. dysarthria and dysphagia, 6. mental retardation, 7. duration of 8 months to 13 years. Pathologically, the three autopsy cases showed very similar features: bilaterally symmetrical necrosis of the caudate nucleus and putamen. These nuclei were involved from the most rostral part to the caudal end. The lesions were strictly confined to almost all the areas within the boundaries of the caudate nucleus and putamen, the intervening portions of the internal capsule being intact. Exceptionally in one case, the anteromedio-ventral part of the head of the striatum, which was considered to be supplied by the anterior cerebral artery, was spared from necrosis. The necrotizing lesions contained well-developed coarse scar formation consisting of gliomesenchymal fibers and progressively reacting astrocytes and microglial cells. The pathogenesis of this peculiar type of striatal necrosis is discussed briefly.

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Zusammenfassung Bericht über fünf Fälle eines seltenen Leidens, das in zwei Familien auftrat. Klinisch boten die Kranken: 1. Beginn in der Kindheit, 2. fehlende anamnestische Hinweise auf anoxische Zwischenfälle oder Intoxikationen, 3. Gangstörungen, 4. Steifheit oder Schlaffheit der Extremitäten, athetotische Bewegungen und Foerstersches Zeichen, 5. Dysarthrie und Dysphagie, 6. psychische Retardation, 7. Krankheitsdauer zwischen 8 Monaten und 13 Jahren. Morphologisch zeigten drei Autopsiefälle sehr ähnliche Befunde: symmetrische Nekrosen des Caudatum und Putamen. Die Kerne waren in ihrer Gesamtheit betroffen. Die Läsionen waren streng auf das Kerngebiet des Caudatum und Putamen beschränkt, während die durchziehenden Abschnitte in der inneren kapsel intakt waren. Nur bei einem Fall war der antero-medio-ventrale Teil des Linsenkernkopfes, der von der A. cerebri anterior versorgt sein dürfte, verschont. Die nekrotisierenden Läsionen umfaßten gut ausgebildete grobe Narbenbildung mit gliös-mesenchymaler Faserwucherung und progressiver Astrogliareaktion sowei Mikrogliazellen. Die Pathogenese dieses eigenartigen Typs von Striatumnekrose wird diskutiert.

     

Infantile bilateral striatal necrosis

Summary A case of infantile bilateral striatal necrosis (IBSN) is reported, the first one found in Scandinavia. Extensive clinical and laboratory investigations did not reveal any evidence of a neurometabolic disease. By computed tomography (CT) degeneration of putamen of either side was detected. The neuropathologic findings included extensive bilateral destruction of the striatum and pallidum and degeneration of the substantia nigra and tegmental nuclei. In the damaged regions, accumulations of cells containing sudanophilic lipids were found and Alzheimer type II glial cells, which were also seen in the cortex. On the basis of the clinical picture and the destruction of nerve cells in particular areas of the brain, in the present case and previously published cases of IBSN, the possible role of glutamatc and other excitotoxic transmitters in the pathogenesis of the disease is discussed.Supported by a grant from Expressens fond för perinatalforskning     

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.     

Infantile bilateral striatal necrosis following measles

A previously healthy 4-year-old boy presented with typical measles and demonstrated lesions confined to basal ganglia. The clinical symptoms were an abrupt onset, impaired consciousness and mutism, extrapyramidal signs and severe neurovegetative dysfunction. No modification of the cerebrospinal fluid was observed; laboratory tests were all normal with the exception of a positive serologic test for measles. Cranial magnetic resonance imaging showed abnormal signals in the striatum, affecting the putamen and the caudate nuclei bilaterally. Neurologic improvement occurred within 2 months, with regression of lesions on cranial imaging, suggesting that edema played an important role in the initial stage of the disease.     

Infantile bilateral striatal necrosis. Clinicopathological classification

Two cases of infantile bilateral striatal necrosis (IBSN) were studied retrospectively, and the literature was reviewed. The two children had presented with progressive neurologic signs of involuntary movements or muscle hypertonia from infancy. Initial computed tomography scans showed mild atrophy of the caudate nuclei or basal ganglia, and the neuropathologic examination revealed diffuse neuronal loss with some patchy preservation and marked astrogliosis in the striatum and globus pallidus. The 27 reported cases of IBSN were divided into three groups with characteristic clinical and pathologic features: early, acute onset (four cases); early, gradual onset (16 cases); and late onset (seven cases). Although metabolic changes in the developing corpus striatum may be important in the pathogenesis of IBSN, the origin is uncertain.     

Reversible parainfectious bilateral "striatal necrosis"

Bilateral striatal necrosis is usually associated with either endogenous or exogenous toxins, and with poor neurodevelopmental outcomes. We describe two patients with acute bilateral striatal clinical syndrome and magnetic resonance signal changes who made a complete clinical and radiologic recovery within 3 months. After an uneventful pregnancy, normal birth, and normal development, both boys presented at ages 3 and 5 years, respectively, after a viral illness with slurring of speech, bradykinesia, and an extrapyramidal movement disorder. On examination, both manifested bilateral cog wheel rigidity, with a broad-based gait and flexor plantar response. Cranial magnetic resonance imaging in both children indicated bilateral, symmetric, high signal changes in the lentiform nucleus, predominately in the putamen, with sparing of the globus pallidi bilaterally. The brain parenchyma was otherwise normal. Neurometabolic investigations produced normal results in both patients. The pathogenesis is uncertain, but could be immune-mediated. Both children, at 3-year and 1-year follow-ups, respectively, are doing well neurologically and academically. Our patients demonstrate that abnormal imaging findings during acute stages do not preclude good clinical and radiologic recovery.     

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.     

Familial infantile myoclonic epilepsy: clinical features in a large kindred with autosomal recessive inheritance

PURPOSE: To describe the clinical features of a large kindred with familial infantile myoclonic epilepsy (FIME) with autosomal recessive inheritance, and to discuss the nosology of the early infantile myoclonic epilepsies (IMEs). METHODS: The family descends from the intermarriage of two couples of siblings. In a previous study, we mapped the genetic locus to chromosome 16p13.We analyzed results of family records and personal history, psychomotor development, neurologic examination, epilepsy features, and EEG recordings for each subject. RESULTS: FIME has a strong penetrance (eight affected of 14 subjects) and a homogeneous clinical picture. Like the benign form of infantile myoclonic epilepsy (BIME), FIME is a true idiopathic IME with unremarkable history, no neurologic or mental impairment, good response to treatment, and normal interictal EEG pattern. Conversely, onset with generalized epileptic seizures without fever (four patients) or with fever (one patient), frequency and duration of the myoclonic seizures, occurrence of generalized tonic--clonic seizures (GTCSs) in all patients and persistence of seizures into adulthood are characteristics of the severe infantile myoclonic epilepsy (SIME). CONCLUSIONS: Clinical overlap probably exists among the myoclonic epilepsies of infancy. FIME differs from other forms of IME in its phenotypic features. The peculiar mode of inheritance is explained by the genetic background of the family. Genetic studies suggest linkage to chromosome 16 in familial cases of true IME.     

Acute bilateral striatal necrosis with rotavirus gastroenteritis and inborn metabolic predisposition

We present a 9-month-old male with acute rotavirus gastroenteritis who developed an acute encephalopathy with focal seizures and developmental regression. Magnetic resonance imaging showed bilateral striatal necrosis and raised glutarylcarnitine levels on tandem mass spectrometry of a (crisis) blood spot, and chromatography of organic acids revealed increased urinary excretion of dicarboxylic acid. Skin biopsy demonstrated a partial decrease in glutaryl-CoA dehydrogenase activity. The case was not typical for either rotavirus encephalitis/rotavirus-associated encephalopathy or for glutaric aciduria type I. The patient has developmental delay and continues to receive physiotherapy, speech therapy, and local developmental follow-up.     

A case report of infantile striatal necrosis with an acute onset

We report here an autopsy case, an 8-year-old boy diagnosed as having infantile striatal necrosis, characterized by a preceding febrile illness followed by acute encephalopathy with abrupt obtundation, seizures and dystonia, with remarkable improvement of the disturbed consciousness and intelligence after TRH-T therapy. These clinical symptoms were linked with bilateral necrosis of the striata on CT scanning. The presented case belonged to a newly described subgroup of the heredogenous disorders that produce necrosis of the putamina in children.     

Progressive supranuclear palsy: clinical features and response to treatment in 16 patients

Among 415 patients with parkinsonism, 16 (3.9%) had findings of progressive supranuclear palsy (PSP). This report reviews the clinical features and response to drug therapy in those 16 patients. Anticholinergic drugs failed to benefit any of the 5 patients treated, while presynaptic dopaminergic drugs (Sinemet or amantadine) were beneficial in only 5 of 22 patient trials. Alternatively, dopamine agonists (bromocriptine and pergolide) caused improvement in 9 of 14 patient trials despite the fact that all but 1 of these patients had previously failed to respond to presynaptic dopaminergic drugs. Dopamine agonists such as bromocriptine and pergolide may be useful in some patients with PSP.     

Catatonia in psychotic patients: clinical features and treatment response

The authors report clinical features and treatment response in 25 patients with catatonia admitted to an inpatient psychiatric unit specializing in psychotic disorders. Electroconvulsive therapy, benzodiazepines, and clozapine had beneficial effects on catatonic features, whereas typical antipsychotics resulted in clinical worsening.     

Transient seizure disappearance due to bilateral striatal necrosis in a patient with intractable epilepsy

An 8-year-old girl had suffered from intractable epilepsy due to cortical dysplasia. She developed mycoplasma pneumonia with massive pleural effusion. Fever continued for 3 weeks. Four weeks after the onset of this infection, she suddenly developed horizontal nystagmus, ataxia, choreoathetotic movements and confusion. CT disclosed swelling and low density of the heads of the caudate nuclei and putamina bilaterally. MRI revealed areas of symmetrical high intensity in the striatum on T2-weighted imaging. These lesions were thought to comprise bilateral striatal necrosis (BSN) mediated by the mycoplasma infection or Wernicke encephalopathy. Six months later, she had completely recovered clinically. During the 6 months after BSN, she did not have any epileptic seizures. Her epileptic seizures reappeared thereafter at a lower frequency. The striatum may be involved in the propagation pathway for epileptic seizure activity in this patient.     

A case of bilateral striatal necrosis associated with vesicular skin eruption

We report here a case of bilateral striatal necrosis associated with vesicular eruption in the generalized skin. A 13-year-old, previously healthy boy had a febrile disease which was treated with antibiotics, anti-inflammatory drugs, and an antiemetic agent. Two days later, generalized vesicular rash appeared. Seven days later, he became dysarthric. Rigidity and paralysis of the legs also developed, followed by mild disturbance of consciousness. Despite treatment with high-dose methylprednisolone and L-dopa, neurological symptoms worsened after admission, with appearance of involuntary movements and dysphagia. One month later, however, they improved spontaneously, and the patient was discharged with minimal sequelae. Cranial magnetic resonance imaging (MRI) demonstrated high signal intensity lesions in the bilateral striatum on both the T1- and T2-weighted images. The dermatologic and neurologic disorders of this case may have resulted from drug allergy, although role of the infection was not excluded completely. The MRI findings may reflect microhemorrhage or necrosis in the striatal lesions.