Paroxysmal extreme pain disorder (previously familial rectal pain syndrome).

OBJECTIVE: To describe the clinical phenotype of paroxysmal extreme pain disorder (previously called familial rectal pain syndrome), an autosomal dominant condition recently shown to be a sodium channelopathy involving SCN9A. METHODS: An international consortium of clinicians, scientists, and affected families was formed. Clinical details of all accessible families worldwide were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. A validated pain questionnaire was completed by 14 affected individuals. RESULTS: Seventy-seven individuals from 15 families were identified. The onset of the disorder is in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate initially, with skin flushing in all and harlequin color change and tonic attacks in most. Dramatic syncopes with bradycardia and sometimes asystole are common. Later, the disorder is characterized by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse. Attacks are triggered by factors such as defecation, cold wind, eating, and emotion. Carbamazepine is effective in almost all who try it, but the response is often incomplete. CONCLUSIONS: Paroxysmal extreme pain disorder is a highly distinctive sodium channelopathy with incompletely carbamazepine-sensitive bouts of pain and sympathetic nervous system dysfunction. It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures.

Hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy.

BACKGROUND: The main hereditary vascular conditions involving both retinal and cerebral vessels include cerebroretinal vasculopathy, HERNS (hereditary endotheliopathy with retinopathy, nephropathy, and stroke), and hereditary vascular retinopathy; all are linked to the same locus on chromosome 3p21. Hereditary retinal arteriolar tortuosity is a distinct, autosomal dominant condition characterized by retinal arteriolar tortuosity and recurrent retinal hemorrhages. This condition is known to affect only retinal vessels. METHODS: Clinical and brain MRI investigations of eight members of a three-generation family and extensive biological and systemic vascular investigations within one affected family member were conducted. RESULTS: Six of eight family members were clinically symptomatic; disorders included infantile hemiparesis (2), migraine with aura (3), and retinal hemorrhage (1). Five individuals had retinal arteriolar tortuosities. A diffuse leukoencephalopathy in association with dilated perivascular spaces was observed in six individuals. Two family members had silent, deep cerebral infarcts as demonstrated on MRI. Genetic linkage analysis strongly suggests that this disorder is not linked to the 3p21 hereditary vascular retinopathy/cerebroretinal vasculopathy/HERNS locus. CONCLUSIONS: The authors describe a novel hereditary autosomal dominant condition affecting both retinal and cerebral vessels and characterized by infantile hemiparesis, migraine with aura, retinal hemorrhage, retinal arterial tortuosity, and leukoencephalopathy with dilatation of perivascular spaces and microbleeds on brain MRI. Investigation of additional families should help to map the gene and to better categorize the spectrum of hereditary cerebroretinal small vessel diseases.

Late-onset mitochondrial DNA depletion: DNA copy number, multiple deletions, and compensation.

Through a report of 4 late-onset cases with mitochondrial DNA (mtDNA) depletion, we address the specificity of the clinical entities associated with a very low residual amount of mtDNA. Three of the patients met the diagnostic criteria of Kearns Sayre syndrome, which has never been associated with mtDNA depletion. The fourth patient had an isolated skeletal myopathy. Deleted mtDNA molecules were found by long-range polymerase chain reaction (PCR) only in the Kearns Sayre syndromes, which strengthens the clinical differences between the two types of patients. All patients had extremely low residual amounts of mtDNA as shown by Southern blot analysis. Using an original method based on competitive PCR, we were able to measure the number of mtDNA copies per diploid genome. These results demonstrated the severity of the depletion in the patients by comparison not only to normal controls but also to patients with mtDNA disorders. Despite the severity of the depletion, in situ hybridization using two mtDNA transcripts revealed a normal steady-state level of transcription. Such compensation provides clues to the striking contrast between the severity of mtDNA depletion and the late onset and slowly progressive disease.

Rapid improvement of intracranial tuberculomas after addition of ofloxacin to first-line antituberculosis treatment.

Reported here is the case of a 9-year-old girl presenting with disseminated tuberculosis, the manifestations of which included mediastinal adenopathy, an osteolytic parietal lesion with a large associated scalp abscess, cerebral empyema, meningoencephalitis, and tuberculomas. No clear improvement was observed after 4 weeks of first-line antituberculosis treatment (10 mg/kg rifampin, 15 mg/kg isoniazid, 30 mg/kg ethambutol, 30 mg/kg pyrazinamide). The isolation of an isoniazid-resistant organism prompted institution of ofloxacin. Introduction of this drug was associated with dramatic improvement. Its good penetration into the central nervous system and its distribution into macrophages suggest that this drug may be of interest for the treatment of intracranial tuberculomas, particularly those due to isoniazid-resistant strains.

Aicardi-Goutières syndrome: monogenic recessive disease, genetically heterogeneous disease, or multifactorial disease?

Aicardi-Goutières syndrome (AGS) is a severe progressive familial encephalopathy, which is usually diagnosed shortly after birth. Using the principle of homozygosity mapping, genome-wide screening of five consanguineous families was performed to search for a homozygous region shared by all affected individuals. A total of 364 markers with an average spacing of 9.9 cM were genotyped, but no homozygous region common to all affected individuals could be found. Regions of homozygosity in affected sibs could only be identified within each family individually. This may reflect genetic heterogeneity, possibly related to clinical heterogeneity, since several syndromes are clinically difficult to distinguish from AGS. Involvement of a small number of genes and/or of an external factor, such as infection, may also explain the absence of a homozygous region common to all affected individuals.

Extensive brain calcification in two children with bilateral Coats' disease.

We report two children with bilateral Coats' disease associated with cerebral calcifications in the basal ganglia and deep white matter, asymptomatic at the time of their discovery. Cerebellar ataxia developed secondarily in one of them. Both children were born small for date and had febrile convulsive seizures. Three similar patients have been previously reported, two of them in the same sibship; the third reported patient died of aplastic anemia. Bilateral Coats' disease in children should prompt systematic CT scan in search of cerebral calcifications. If present, neurological and genetic prognosis should be cautious.

Surgery of epilepsy associated with focal lesions in childhood.

OBJECT: Surgery in children with epilepsy is a new, evolving field. The important practical issues have been to define strategies for choosing the most suitable candidates and the type and optimal timing of epilepsy surgery. This study was undertaken to elucidate these points. METHODS: To identify the factors that correlated with outcome, the authors analyzed a series of 200 children (aged 1-15 years (mean 8.7 years) who underwent surgery between 1981 and 1996 at the Hôpital Necker-Enfants Malades. In 171 cases (85.5%) the epilepsy was medically refractory and was associated with focal cortical lesions. Surgery consisted of resection of the lesion without specifically attempting to identify and remove the "epileptogenic area. "In the group of children whose seizures were medically refractory, the mean follow-up period was 5.8 years. According to Engel's classification, 71.3% of these children became seizure free (Class 1a,) whereas 82% were in Class I. A multivariate statistical analysis revealed that among all the factors studied, the success of surgery in a patient in whom there was a good clinical/electroencephalogram/imaging correlation depended on the patient's having undergone a minimally traumatic operation, a complete resection of the lesion, and a short preoperative seizure duration. After the surgical control of epilepsy, behavior disorders were more improved (31% of all patients) than cognitive function (25%). The patient age at onset, duration and frequency of seizures, intractability of the disease to therapy, and seizure characteristics were correlated with cognitive, behavioral, and academic performance pre- and postoperatively. Multivariate statistical analysis revealed that cognitive dysfunction correlated highly with the duration of epilepsy prior to surgery, whereas behavioral disorders correlated more with seizure frequency. CONCLUSIONS: These data must be taken into account when selecting patients for surgical treatment and when deciding the timing of surgery. Early surgical intervention allows for optimum brain development.

Hemifacial spasm or subcortical epilepsy?

A child with Goldenhar's syndrome presented at about one week of age with stereotyped, repetitive paroxysmal episodes of hemifacial contraction, suggestive of partial seizures or hemifacial spasm. Later in life he also developed independent, permanent abnormal eye and chin movements identical in rhythm to those seen in myorhythmias, suggesting involvement of the dentato-olivary pathway. MRI demonstrated a hamartomatous lesion at the level of the pontomedullary junction. We speculate that the nature of the lesion could be responsible for the partial seizures mimicking hemifacial spasm and that because of its location, this same lesion could also be implicated in the genesis of myorhythmias. The presence of a hamartomatous lesion in a region affected by the abnormal development of the first and second branchial arches is not fortuitous.

Aicardi-Goutières syndrome: an update and results of interferon-alpha studies.

Twenty-seven patients with familial encephalopathy with calcification of the basal ganglia and chronic cerebrospinal fluid (CSF) lymphocytosis (Aicardi-Goutières syndrome) are reviewed. In 19 children, the onset was within the first 4 months of life. Most patients had normal head circumference at birth, but 21 developed microcephaly between 3 and 12 months. Neuroimaging showed severe and progressive brain atrophy in all patients. The extent and intensity of the calcification was variable even in the same sibship. CSF lymphocytosis persisted beyond 12 months of age in 7 children. High levels of interferon-alpha were found in serum and CSF in 14 patients. The higher CSF levels suggest intrathecal synthesis. Tubuloreticular inclusions related to the presence of interferon were found in 4 additional children. The 19 patients still alive (6 older than 10 years) are profoundly disabled. However, the syndrome may present with individual variations in severity, rapidity of evolution, and imaging features. Neuropathological examination in 2 patients failed to detect significant inflammatory lesions and showed only foci of necrosis and wide-spread demyelination. This study supports an autosomal recessive inheritance for this syndrome. The high level of interferon-alpha is not explained but may play a role in the pathogenesis of the disorder.

Moyamoya disease in a child with glycogen storage disease type Ia.

A three-year-old child affected by glycogen storage disease (GSD) type Ia presented with acute hemiplegia secondary to Moyamoya disease. So far, the association of moyamoya with GSD Ia had only been reported twice. The rarity of both conditions makes their association unlikely to be a chance event and an etiological relationship between them must be considered.

Leukoencephalopathy, megalencephaly, and mild clinical course. A recently individualized familial leukodystrophy. Report on five new cases.

Five children presented in the first months of life with progressive megalencephaly and leukodystrophy characterized by diffuse swelling of the white matter, cystic cavitations in frontal and temporal lobes, and a slow progressive course contrasting with the intensity of the leukodystrophic process. Four had epilepsy. Two were brothers and three had consanguineous parents. No metabolic defect was detected. The clinical and magnetic resonance imaging features are similar to those of patients previously reported. These five new cases add arguments to delineate a new type of leukodystrophy with megalencephaly in infancy and autosomal recessive inheritance.

Extensive brain calcifications, leukodystrophy, and formation of parenchymal cysts: a new progressive disorder due to diffuse cerebral microangiopathy.

A new cerebral disorder, described in three unrelated children, has recognizable clinical, radiologic, and neuropathologic findings. The onset occurs from early infancy to adolescence with slowing of cognitive performance, rare convulsive seizures, and a mixture of extrapyramidal, cerebellar, and pyramidal signs. CT shows progressive calcifications in the basal and cerebellar gray nuclei and the central white matter. MRI reveals diffuse abnormal signals of the white matter on T2-weighted sequences. A special feature is the development of parenchymal cysts in the cerebellum and the supratentorial compartment, leading to compressive complications and surgical considerations. Neuropathologic examination of surgically removed pericystic samples reveals angiomatous-like rearrangements of the microvessels, together with degenerative secondary changes of other cellular elements. Both the anatomic findings and the course of the disease suggest a constitutional, diffuse cerebral microangiopathy resulting in microcystic, then macrocystic, parenchymal degeneration.

Extensive macrogyri or no visible gyri: distinct clinical, electroencephalographic, and genetic features according to different imaging patterns.

We studied 43 children with extensive brain gyral anomalies diagnosed radiologically and defined by (a) the absence or paucity of sulci over cortical areas affecting at least two lobes in each hemisphere, and (b) the absence or reduction of interdigitation between gray and white matter. We correlated the clinical, EEG, and genetic findings with the imaging features. A seemingly homogeneous group of patients (group A, n = 30) presented a common imaging pattern characterized by four features: (1) a thickened neocortex, (2) widened lateral ventricles, (3) apparent verticalization and widening of sylvian fissures, and (4) bilateral and symmetric distribution of the abnormalities. Another group of patients (group B, n = 13) exhibited heterogeneous imaging anomalies, termed "nonlissencephalic brain malformation," differing in at least one of the following four ways from the radiologic criteria defining group A: absence of verticalization of sylvian fissures (n = 12), thin neocortex (n = 2), normal-size lateral ventricles (n = 2), and asymmetric brain defects (n = 3). In group A, some clinical features had a significantly lower frequency (p < or = 0.01) than in group B: microcephaly, a complete lack of postural development, and intractable epilepsy. There was a significant relationship, but only in group A, between the degree of gyral anomalies and the extent of neurodevelopmental delay. Some EEG patterns (rapid rhythms and delta-theta rhythms) were highly specific for the group A patients. There was lower risk of familial recurrence in group A (recurrence of convolutional anomalies was 3.5% of sibship in group A versus 44% of sibship in group B, p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Deletion of mitochondrial DNA in patient with chronic tubulointerstitial nephritis.

We report a mitochondrial DNA deletion (2.6 kb) in a boy with tubulointerstitial nephritis in whom chronic renal failure and leukodystrophy subsequently developed. Elevated lactate values in plasma and cerebrospinal fluid were suggestive of a defect in the mitochondrial respiratory chain. High amounts of deleted mitochondrial DNA were present in muscle and cerebral white matter. On the basis of this observation, we suggest giving consideration to genetic defects of oxidative phosphorylation in any attempt to determine the origin of unexplained chronic tubulointerstitial nephritis, especially when seemingly unrelated organs are involved.

Three new cases of the Schinzel-Giedion syndrome and review of the literature.

Three fetuses with normal chromosomes were found to have uni- or bilateral hydronephrosis during the third trimester of pregnancy. At birth, they presented with coarse face, hypertelorism, and a deep groove under the eyes. Fontanelles and sutures were wide open. Genital abnormalities were present in 2 cases. Skeletal radiographs showed delayed bone maturation, broad and dense ribs, and a wide synchondrosis between the exoccipital and supraoccipital bones. The combination of such findings suggested the diagnosis of Schinzel-Giedion syndrome. Two patients died soon after birth, whereas the third one developed severe mental and motor retardation with seizures and spasticity, and died at 18 months. Schinzel-Giedion syndrome is rare and likely to be inherited as an autosomal recessive trait. So far, 13 well-documented cases have been reported allowing major and minor traits of the syndrome to be distinguished. Since no genetic marker is available, the prenatal diagnosis of Schinzel-Giedion syndrome relies on ultrasound examination, especially detection of renal abnormalities.

[GM2-Gangliosidosis variant B1 disclosed during adolescence by an isolated multi-systemic involvement of the central and peripheral nervous systems]. / Gangliosidose à GM2 variant B1. Révélation à l'adolescence par une atteinte isolée et plurisystématisée du système nerveux central et périphérique.

The authors report on a Portuguese family with 3 adult brothers affected with GM2-gangliosidosis (B1 variant) in a sibship of 4, and more specifically on one of these brothers with neurological onset at the age of 17. Psychosis, lower motoneuron involvement and dysarthria were predominant in two of the cases; the third had a cerebellar symptomatology. Hexosaminidase A activity, studied in leukocytes, was profoundly deficient when measured using the specific sulfated substrate, but nearly normal using a conventional assay (non-sulfated substrate). These results established the diagnosis of the unusual enzymological form of GM2-gangliosidosis known as the B1 variant, which had so far not been associated with an adult phenotype. Molecular studies are in progress to study genotype/phenotype correlations in this family in comparison with known mutations in the B1 variant and in adult GM2-gangliosidosis. This report also emphasizes that a metabolic etiology, leading to genetic counselling, should be considered in some familial degenerative neurological disorders.

Alternating hemiplegia of childhood.

We report 22 cases of alternating hemiplegia of childhood. In addition to repeated episodes of hemiplegia lasting from a few minutes to several days, the disease was characterized by an onset before 18 months of age, the occurrence of tonic or dystonic attacks, nystagmus, dyspnea and other autonomic phenomena, and the development of cognitive impairment and of a choreoathetotic movement disorder. All the patients also had episodes of quadriplegia that occurred either when a hemiplegia was shifting from one side to the other or as an isolated manifestation. Such episodes were often severe and followed by developmental deterioration. In all children, sleep consistently relieved both weakness and associated paroxysmal phenomena, but these would reappear 10 to 20 minutes after the children awakened, during long-lasting episodes. Although six patients also had epileptic seizures, the condition seems to be distinct from epilepsy, and the clinical features and poor outcome differentiate it from migraine. Treatment with the calcium-entry blocker flunarizine was partially effective.

Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome.

We report 2 sisters with a degenerative neurological disorder presenting clinically as a leukodystrophy. CT scan and MRI demonstrated small symmetrical foci of necrosis in the substentia nigra and in the basal ganglia typical of Leigh syndrome and diffuse cerebral white matter abnormalities. In these patients a deficiency in complex II of the respiratory chain was demonstrated in isolated mitochondria from muscle, as well as in fibroblasts and lymphocytes.