Leukoencephalopathy with calcifications and cysts (LCC): 5 cases and literature review.

INTRODUCTION: Leukoencephalopathy with calcifications and cysts (LCC) is a rare autosomal recessive cerebral angiomatous-like microangiopathy characterized by diffuse and asymmetric white-matter lesions associated with multiple calcifications and cysts. The disease is caused by SNORD118 mutations. The entire clinical spectrum of LCC is not yet fully determined. MATERIAL AND METHODS: To define the clinical spectrum of LCC, we analyzed data from recently diagnosed cases and from the litterature. Both clinical and imaging features from our five LCC cases harboring compound heterozygous SNORD118 mutations were presented and all cases reported in the litterature reviewed. RESULTS: Ninety-two LCC cases including our five patients were identified. Consanguinity was rare (4%), and 97% of cases were symptomatic. Mean age of first clinical manifestations was 16.1±16.1 years (range 1 month-71 years) and was earlier in men (10.3±14.3 years) than in women (20.2±22.8 years) (P=0.02). The main inaugural symptoms were seizures (36%; mean age at onset: 5.2±9.5 years) and progressive neurological symptoms including ataxia, dystonia and spasticity (26%; 27.8±23.6 years). Intracranial hypertension was less frequently observed (14%), mostly in adults (mean age 31.5±13.2 years). Ischemic or hemorrhagic strokes were inaugural symptoms in two adults (2%). During follow-up, most patients developed progressive extrapyramidal, cerebellar and pyramidal signs (83%), cognitive decline (56%), seizures (37%), intracranial hypertension (30%) or stroke (2%). CONCLUSION: In LCC, the clinical spectrum is largely heterogeneous and the course of the disease appears highly variable in contrast to other hereditary cerebral small vessel diseases.

A novel large deletion in CCM1 gene in a Tunisian family.

Familial CCM is a rare entity associated with the mutation of three genes: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10). We report here the first description of a Tunisian familial CCMs composed of six members. The father and two daughters were affected and symptomatic. The two other kindred were healthy. Surgical treatment was performed in only one affected patient. Molecular analysis of KRIT1, MGC4607 and PDCD10 genes identified a large KRIT1 deletion of the first ten exons. To the best of our knowledge, this large deletion has never been reported before.

Cerebro-retinal microangiopathy with calcifications and cysts due to recessive mutations in the CTC1 gene.

Cerebro-retinal microangiopathy with calcifications and cysts (CRMCC) or Coats plus syndrome is a pleiotropic disorder affecting the eyes, brain, bone and gastrointestinal tract. Its primary pathogenesis involves small vessel obliterative microangiopathy. Recently, autosomal recessively inherited mutations in CTC1 have been reported in CRMCC patients. We herein report an adolescent referred to our hospital following new seizures in a context of an undefined multisystem disorder. Cerebral imaging disclosed asymmetrical leukopathy, intracranial calcifications and cysts. In addition, he presented other typical CRMCC features i.e. a history of intrauterine growth retardation, skeletal demineralization and osteopenia, bilateral exudative vitreo-retinopathy reminiscent of Coats disease, recurrent gastrointestinal hemorrhages secondary to watermelon stomach and variceal bleeding of the esophagus due to idiopathic portal hypertension and telangiectatic and angiodysplasic changes in the small intestine and colon, and anemia due to recurrent bleeding and bone marrow abnormalities. The patient was diagnosed with Coats plus syndrome. CTC1 gene screening confirmed the diagnosis with the identification of heterozygous deleterious mutations. CRMCC due to CTC1 mutations has a broad clinical expressivity. Our case report illustrates the main possible associated phenotypes and their complications, demonstrating the need for a careful etiological search in order to initiate appropriate therapeutic and preventive measures.

Occurrence of multiple Cerebral Cavernous Malformations in a patient with Neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis 1 (NF1) belongs to the autosomal dominant neurocutaneous disorders' group, which mainly includes NF1 and NF2, tuberous sclerosis, von Hippel-Lindau disease and Cerebral Cavernous Malformations (CCMs). NF1 has a major impact on the nervous system, eye, skin, bone or cardiovascular system. Cerebrovascular lesions have been reported in NF1 including aneurysm, pseudoaneurysm, arteriovenous malformations, vascular stenosis or occlusion and Moya moya syndrome. OBJECTIVE: To report a case of an NF1 patient with multiple CCMs. OBSERVATION: A 47-year-old man with café-au-lait skin lesions, countless cutaneous neurofibromas, short stature and scoliosis was admitted for progressive spinal cord compression due to histologically proven neurofibroma. Systematic cerebral MRI screening including gradient echo sequences showed multiple asymptomatic CCMs. Screening of CCM1, CCM2 and CCM3 genes was negative while a deleterious frameshift mutation was identified in NF1 gene. CONCLUSION: While single CCM can occur in NF1 patients following radiation exposure, they are only rarely reported in non-irradiated NF1 brain. Even if it could be a fortuitous association, plausible links and explanations exist. If cerebral MRI can be systematic in NF1 to detect asymptomatic gliomas, used protocols in neuroradiology do not usually include gradient echo sequences, the most sensitive test for CCM detection, leading possibly to failure to detect these vascular lesions. More reports having this combination and further investigations of NF1 families will certainly provide a better understanding of links between these 2 phakomatoses, as recently reported with "multiple meningiomas" phenotype associated with multiple CCMs in patients with CCM3 gene mutations or café-au-lait skin lesions in CCM1 mutation carriers.

Deep intronic KRIT1 mutation in a family with clinically silent multiple cerebral cavernous malformations.

Loss-of-function mutations in CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations (CCMs). However, genomic DNA sequencing combined to large rearrangement screening fails to detect a mutation in 5% of those cases. We report a family in which CCM lesions were discovered fortuitously because of the investigation of a developmental delay in a boy. Three members of the family on three generations had typical multiple CCM lesions and no clinical signs related to CCM. No mutation was detected using genomic DNA sequencing and quantitative multiplex PCR of short fluorescent fragments (QMPSF). cDNA sequencing showed a 99-nucleotide insertion between exons 5 and 6 of CCM1, resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that activates a cryptic splice site. This pseudoexon leads to a premature stop codon. These data highly suggest that deep intronic mutations explain part of the incomplete mutation detection rate in CCM patients and underline the importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests. This kind of mutation may be responsible for apparent sporadic presentations due to a reduced penetrance.

CCM3 Mutations Are Associated with Early-Onset Cerebral Hemorrhage and Multiple Meningiomas.

Mutations of CCM3/PDCD10 cause 10-15% of hereditary cerebral cavernous malformations. The phenotypic characterization of CCM3-mutated patients has been hampered by the limited number of patients harboring a mutation in this gene. This is the first report on molecular and clinical features of a large cohort of CCM3 patients. Molecular screening for point mutations and deletions was used to identify 54 CCM3-mutated index patients. Age at referral and clinical onset, type of inaugural events and presence of extra-axial lesions were investigated in these 54 index patients and 22 of their mutated relatives. Mean age at clinical onset was 23.0 ± 16 years. Clinical onset occurred before 10 years in 26% of the patients, and cerebral hemorrhage was the initial presentation in 72% of these patients. Multiple extra-axial, dural-based lesions were detected in 7 unrelated patients. These lesions proved to be meningiomas in 3 patients who underwent neurosurgery and pathological examination. This 'multiple meningiomas' phenotype is not associated with a specific CCM3 mutation. Hence, CCM3 mutations are associated with a high risk of early-onset cerebral hemorrhage and with the presence of multiple meningiomas.

PRRT2 mutations and paroxysmal disorders.

In the past year, mutations in the PRRT2 gene have been identified in patients with paroxysmal kinesigenic dyskinesia and other paroxysmal disorders. We conducted a review of the literature on PRRT2 mutation-associated disorders. Our objectives were to describe the wide clinical spectrum associated with PRRT2 mutations, and to present the current hypotheses on the underlying pathophysiology. PRRT2 mutations are associated with a wide range of clinical syndromes: the various paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, episodic ataxia and even intellectual disability in the homozygous state. The PRRT2 protein, through its interaction with SNAP-25, could play a role in synaptic regulation in the cortex and the basal ganglia. The pathogenesis may be caused by PRRT2 loss of function, which may induce synaptic deregulation and neuronal hyperexcitability. However, this does not explain the phenotypic variability, which is likely modulated by environmental factors, modifier genes or age-dependent expression. The clinical spectrum of PRRT2 mutations has expanded among paroxysmal disorders and beyond. Unraveling the molecular pathways linking the genetic defect to its clinical expression will be crucial for the diagnosis and treatment of these disorders.

[Hereditary episodic ataxia]. / Ataxies épisodiques génétiques.

INTRODUCTION: Episodic ataxia (EA) designates a group of autosomal dominant channelopathies that manifest as paroxysmal attacks of imbalance and incoordination. EA conditions are clinically and genetically heterogeneous. Seven types of EA have been reported so far but the majority of clinical cases result from two recognized entities. STATE OF ART: Episodic ataxia type 1 (EA1) is characterized by brief episodes of ataxia and dysarthria, and interictal myokymia. Onset occurs during the first two decades of life. Associated epilepsy has been reported in some EA1 patients. EA1 is caused by mutations of the KCNA1 gene coding for the voltage-gated potassium channel Kv1.1. Mutation is mostly missense mutations. Acetazolamide, a carbonic-anhydrase inhibitor, may reduce the frequency and severity of the attacks in some but not all affected individuals. Episodic ataxia type 2 (EA2) is characterized by episodes lasting longer than in EA1, that manifest by ataxia, dysarthria, vertigo, and also, in most of the cases, an interictal nystagmus. Other clinical features as developmental delay or epilepsy can be present in some patients. Brain MRI shows frequently a vermian atrophy. Onset occurs typically in childhood or early adolescence, but can sometimes be in adulthood. EA2 is caused by mutations in CACNA1A, a gene coding for the neuronal voltage-gated calcium channel Cav1.1. For two-thirds of the cases, mutations lead to a stop codon. This type is most often responsive to acetazolamide that reduces the frequency and severity of attacks, but does not appear to prevent the progression of interictal symptoms. PERSPECTIVES: This article summarizes current knowledge on episodic ataxia type 1 and 2 and describes briefly the other types of EA. CONCLUSION: Molecular analysis of KCNA1 or CACNA1A provides a confirmation of the diagnosis of EA1 and EA2. Other types remain rare phenotypic variants. Among them, only two genes have been identified: CACNB4 in EA5 and SLC1A3 in EA6 and mutations have been found in a very few cases. No mutation can be detected in some familial cases of episodic ataxia, suggesting further heterogeneity.

De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine.

OBJECTIVE: Hemiplegic migraine (HM) is a rare subtype of migraine with aura that may occur as a familial (FHM) or sporadic condition (SHM). Screening of FHM genes in previous series of patients with SHM detected a very low proportion of mutated patients. In this study, we investigated the FHM genes in patients with an early onset sporadic form of HM (onset before 16 years). METHODS: Twenty-five patients were included. Each one and his or her 2 parents were blood sampled. Mean age at diagnosis was 14.7 ± 8.2 years and mean age at clinical onset was 7.7 ± 3.4 years. Sequencing of ATP1A2 and CACNA1A was conducted in each proband and all identified variants were looked for in both parents. SCN1A was screened in all patients without CACNA1A or ATP1A2 de novo mutation. RESULTS: Twenty-three different amino acid variants were identified in 23 of the 25 patients. The variants occurred de novo in 19 patients (76%), strongly in favor of their causal role. SCN1A analysis did not show any mutation. Among the 19 patients with a de novo mutation, 5 had a pure HM and 14 had associated neurologic signs such as ataxia, epilepsy, or intellectual disabilities. CONCLUSIONS: FHM genes are involved in early-onset SHM, in particular when associated with neurologic signs. Molecular analysis can be helpful in those cases. Our study identified 14 novel de novo mutations that will help to interpret genetic tests in molecular diagnosis practice.

Episodic ataxia type 2: unusual aspects in clinical and genetic presentation. Special emphasis in childhood.

OBJECTIVE: To describe aspects in clinical and genetic presentation in five patients with episodic ataxia type 2 (EA2). METHODS: CACNA1A gene screening identified a mutation in three probands and in two of their children. RESULTS: The three probands had attacks of imbalance, associated with dizziness/vertigo and/or headache. Two of them had independent migraine attacks. Interictal oculomotor examination revealed a gaze evoked nystagmus and central oculomotor signs. Two probands had a history of strabismus. All responded well to acetazolamide. Two children were found to have both clinical and genetic abnormalities. At 23 months, one child started to have short attacks of imbalance mimicking benign paroxysmal vertigo of childhood. Then, the frequency and duration of his attacks increased and some were associated with headache. The other child developed permanent imbalance with falls at the age of 2 years, strabismus, hyperactivity and slight to moderate cognitive deficiency. When aged 10 years, this was further complicated by episodic ataxia. Genetic analysis revealed three novel mutations in the calcium channel gene CACNA1A (chromosome 19p13). The two children had the same genetic abnormality as their parents. CONCLUSION: EA2 may present with still unknown genetic mutations in adults, and with large and various phenotypes in children, such as short attacks of imbalance or permanent imbalance, cognitive deficiency, and possibly strabismus and hyperactivity.

The FHM1 mutation S218L: a severe clinical phenotype? A case report and review of the literature.

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura that is characterized by motor weakness during attacks. FHM1 is associated with mutations in the CACNA1A gene located on chromosome 19. We report a severe, prolonged HM attack in a young pregnant patient who had the S218L FHM1. This CACNA1A mutation has been associated with HM, delayed cerebral oedema and coma following minor head trauma. The case history we report suggests a specific, severe phenotype and the co-occurrence of HM and epilepsy related to the S218L FHM1 mutation.

Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations.

OBJECTIVE: Familial hemiplegic migraine (FHM) is a genetically heterogeneous disorder in which three genes, CACNA1A, ATP1A2, and SCN1A, are currently known to be involved. FHM is occasionally associated with other neurologic symptoms such as cerebellar ataxia or epileptic seizures. A unique eye phenotype of elicited repetitive daily blindness (ERDB) has also been reported to be cosegregating with FHM in a single Swiss family. METHODS: We report an additional family in whom the proband had, in addition to FHM, typical ERDB. In this family and the previously reported Swiss family, the whole coding region of the SCN1A gene was screened after exclusion of mutation in CACNA1A and ATP1A2 genes. RESULTS: We identified two novel SCN1A mutations (c.4495T>C/p.Phe1499Leu and c.4467G>C/p.Gln1489His missense substitutions) in exons 24 and 23, respectively, segregating with the disease in all living affected members. Both mutations were absent from 180 healthy Caucasian controls and were located in an intracellular loop highly conserved throughout evolution. CONCLUSION: We report new clinical data supporting cosegregation of familial hemiplegic migraine and the new eye phenotype of elicited repetitive daily blindness and two novel SCN1A mutations as the underlying genetic defect in two unrelated families. SCN1A encodes the voltage-gated sodium channel Nav1.1 that is highly expressed in the CNS including the retina. This remarkably stereotyped new eye phenotype has clinical characteristics of abnormal propagation of the retinal electrical signal that may be a retinal spreading depression. These results suggest that SCN1A mutations, which alter neuronal brain excitability, may occasionally alter retinal cell excitability.

Late onset hereditary episodic ataxia.

OBJECTIVE: Episodic ataxias (EA) are hereditary paroxysmal neurological diseases with considerable clinical and genetic heterogeneity. So far seven loci have been reported and four different genes have been identified. Analysis of additional sporadic or familial cases is needed to better delineate the clinical and genetic spectrum of EA. METHODS: A two generation French family with late onset episodic ataxia was examined. All consenting family members had a brain MRI with volumetric analysis of the cerebellum. Haplotype analysis was performed for the EA2 locus (19p13), the EA5 locus (2q22), the EA6 locus (5p13) and the EA7 locus (19q13). Mutation screening was performed for all exons of CACNA1A (EA2), EAAT1 (EA6) and the coding sequence of KCNA1 (EA1). RESULTS: Four family members had episodic ataxia with onset between 48 and 56 years of age but with heterogeneity in the severity and duration of symptoms. The two most severely affected had daily attacks of EA with a slowly progressive and disabling permanent cerebellar ataxia and a poor response to acetazolamide. Brain MRI showed in three affected members a decrease in the ratio of cerebellar volume:total intracranial volume, indicating cerebellar atrophy. No deleterious mutation was found in CACNA1A, SCA6, EAAT1 or KCNA1. In addition, the EA5 locus was excluded. CONCLUSIONS: A new phenotype of episodic ataxia has been described, characterised clinically by a late onset and progressive permanent cerebellar signs, and genetically by exclusion of the genes so far identified in EA.

Severe attacks of familial hemiplegic migraine, childhood epilepsy and ATP1A2 mutation.

We studied four members of a family suffering from typical attacks of familial hemiplegic migraine (FHM) caused by a new mutation, R548C, of ATP1A2 gene in exon 12. One individual had also childhood absence epilepsy and generalized tonic-clonic seizures (GTCS). GTCS were followed by a severe attack of hemiplegic migraine at four times. Sodium valproate enabled control of both the epileptic seizures and the most severe FHM attacks. This association of FHM and epileptic seizures and their control with the same treatment suggest similar pathophysiological mechanisms.

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.

PRAM-1 is a novel adaptor protein regulated by retinoic acid (RA) and promyelocytic leukemia (PML)-RA receptor alpha in acute promyelocytic leukemia cells.

The t(15;17) translocation, found in 95% of acute promyelocytic leukemia, encodes a promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARalpha) fusion protein. Complete remission of acute promyelocytic leukemia can be obtained by treating patients with all-trans retinoic acid, and PML-RARalpha plays a major role in mediating retinoic acid effects in leukemia cells. A main model proposed for acute promyelocytic leukemia is that PML-RARalpha exerts its oncogenic effects by repressing the expression of retinoic acid-inducible genes critical to myeloid differentiation. By applying subtraction cloning to acute promyelocytic leukemia cells, we identified a retinoic acid-induced gene, PRAM-1 (PML-RARalpha target gene encoding an Adaptor Molecule-1), which encodes a novel adaptor protein sharing structural homologies with the SLAP-130/fyb adaptor. PRAM-1 is expressed and regulated during normal human myelopoiesis. In U937 myeloid precursor cells, PRAM-1 expression is inhibited by expression of PML-RARalpha in the absence of ligand and de novo superinduced by retinoic acid. PRAM-1 associates with other adaptors, SLP-76 and SKAP-55HOM, in myeloid cell lines and with protein tyrosine kinase lyn. By providing the first evidence that PML-RARalpha dysregulates expression of an adaptor protein, our data open new insights into signaling events that are disrupted during transformation by PML-RARalpha and induced by retinoic acid during de novo differentiation of acute promyelocytic leukemia cells.

Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is a small-artery disease of the brain caused by NOTCH3 mutations that lead to an abnormal accumulation of NOTCH3 within the vasculature. We aimed to establish whether immunostaining skin biopsy samples with a monoclonal antibody specific for NOTCH3 could form the basis of a reliable and easy diagnostic test. We compared the sensitivity and specificity of this method in two groups of patients suspected of having CADASIL with complete scanning of mutation-causing exons of NOTCH3 (in a retrospective series of 39 patients) and with limited scanning of four exons that are mutation hotspots (prospective series of 42 patients). In the retrospective series skin biopsy was positive in 21 (96%) of the 22 CADASIL patients examined and negative in all others; in the prospective series, seven of the 42 patients had a positive skin biopsy whereas only four had a mutation detected by limited NOTCH3 scanning. Our immunostaining technique is highly sensitive (96%) and specific (100%) for diagnosis of CADASIL.