Kufs disease due to mutation of CLN6: clinical, pathological and molecular genetic features.

Kufs disease is the major adult form of neuronal ceroid lipofuscinosis, but is rare and difficult to diagnose. Diagnosis was traditionally dependent on the demonstration of characteristic storage material, but distinction from normal age-related accumulation of lipofuscin can be challenging. Mutation of CLN6 has emerged as the most important cause of recessive Kufs disease but, remarkably, is also responsible for variant late infantile ceroid lipofuscinosis. Here we provide a detailed description of Kufs disease due to CLN6 pathogenic variants. We studied 20 cases of Kufs disease with CLN6 pathogenic variants from 13 unrelated families. Mean age of onset was 28 years (range 12-51) with bimodal peaks in teenage and early adult life. The typical presentation was of progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures. Patients became wheelchair-bound with a mean 12 years post-onset. Ataxia was the most prominent motor feature. Dementia appeared to be an invariable accompaniment, although it could take a number of years to manifest and occasionally cognitive impairment preceded myoclonic seizures. Patients were usually highly photosensitive on EEG. MRI showed progressive cerebral and cerebellar atrophy. The median survival time was 26 years from disease onset. Ultrastructural examination of the pathology revealed fingerprint profiles as the characteristic inclusions, but they were not reliably seen in tissues other than brain. Curvilinear profiles, which are seen in the late infantile form, were not a feature. Of the 13 unrelated families we observed homozygous CLN6 pathogenic variants in four and compound heterozygous variants in nine. Compared to the variant late infantile form, there was a lower proportion of variants that predicted protein truncation. Certain heterozygous missense variants in the same amino acid position were found in both variant late infantile and Kufs disease. There was a predominance of cases from Italy and surrounding regions; this was partially explained by the discovery of three founder pathogenic variants. Clinical distinction of type A (progressive myoclonus epilepsy) and type B (dementia with motor disturbance) Kufs disease was supported by molecular diagnoses. Type A is usually caused by recessive pathogenic variants in CLN6 or dominant variants in DNAJC5. Type B Kufs is usually associated with recessive CTSF pathogenic variants. The diagnosis of Kufs remains challenging but, with the availability of genetic diagnosis, this will largely supersede the use of diagnostic biopsies, particularly as biopsies of peripheral tissues has unsatisfactory sensitivity and specificity.

Focal myositis with neurogenic atrophy: A case report.

Focal myositis is a very rare form of inflammatory myopathy, with unknown etiology. We describe a 44-year-old previously healthy man who noticed a painless swelling on his left forearm, following trauma over the left cubital fossa. The swelling grew progressively over 2 years. He had otherwise no weakness complaints. Physical and neurological examinations were otherwise normal. Creatine kinase and aldolase levels were increased (1,009 U/L and 11.9 U/L, respectively); autoimmunity panel was negative. MRI showed diffuse edema and gadolinium enhancement of muscles innervated by the median nerve. EMG revealed repetitive complex discharges and patterns of continuous muscular activity. The mass was biopsied disclosing findings consistent with focal myositis. Focal myositis with muscular atrophy is a rare situation; the inflammatory mechanism is yet to be defined, but it seems to be a situation with slow progression, with tendency to stabilization.
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Lafora disease.

Lafora disease (LD) is an autosomal recessive progressive myoclonus epilepsy due to mutations in the EPM2A (laforin) and EPM2B (malin) genes, with no substantial genotype-phenotype differences between the two. Founder effects and recurrent mutations are common, and mostly isolated to specific ethnic groups and/or geographical locations. Pathologically, LD is characterized by distinctive polyglucosans, which are formations of abnormal glycogen. Polyglucosans, or Lafora bodies (LB) are typically found in the brain, periportal hepatocytes of the liver, skeletal and cardiac myocytes, and in the eccrine duct and apocrine myoepithelial cells of sweat glands. Mouse models of the disease and other naturally occurring animal models have similar pathology and phenotype. Hypotheses of LB formation remain controversial, with compelling evidence and caveats for each hypothesis. However, it is clear that the laforin and malin functions regulating glycogen structure are key. With the exception of a few missense mutations LD is clinically homogeneous, with onset in adolescence. Symptoms begin with seizures, and neurological decline follows soon after. The disease course is progressive and fatal, with death occurring within 10 years of onset. Antiepileptic drugs are mostly non-effective, with none having a major influence on the progression of cognitive and behavioral symptoms. Diagnosis and genetic counseling are important aspects of LD, and social support is essential in disease management. Future therapeutics for LD will revolve around the pathogenesics of the disease. Currently, efforts at identifying compounds or approaches to reduce brain glycogen synthesis appear to be highly promising.

Diagnosis and misdiagnosis of adult neuronal ceroid lipofuscinosis (Kufs disease).

OBJECTIVE: To critically re-evaluate cases diagnosed as adult neuronal ceroid lipofuscinosis (ANCL) in order to aid clinicopathologic diagnosis as a route to further gene discovery. METHODS: Through establishment of an international consortium we pooled 47 unsolved cases regarded by referring centers as ANCL. Clinical and neuropathologic experts within the Consortium established diagnostic criteria for ANCL based on the literature to assess each case. A panel of 3 neuropathologists independently reviewed source pathologic data. Cases were given a final clinicopathologic classification of definite ANCL, probable ANCL, possible ANCL, or not ANCL. RESULTS: Of the 47 cases, only 16 fulfilled the Consortium's criteria of ANCL (5 definite, 2 probable, 9 possible). Definitive alternate diagnoses were made in 10, including Huntington disease, early-onset Alzheimer disease, Niemann-Pick disease, neuroserpinopathy, prion disease, and neurodegeneration with brain iron accumulation. Six cases had features suggesting an alternate diagnosis, but no specific condition was identified; in 15, the data were inadequate for classification. Misinterpretation of normal lipofuscin as abnormal storage material was the commonest cause of misdiagnosis. CONCLUSIONS: Diagnosis of ANCL remains challenging; expert pathologic analysis and recent molecular genetic advances revealed misdiagnoses in >1/3 of cases. We now have a refined group of cases that will facilitate identification of new causative genes.

Histopathological evidence of Fabry disease in a female patient with left ventricular noncompaction.

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase gene. The most frequent cardiac presentation of Fabry disease is cardiomyopathy characterized by left ventricular (LV) hypertrophy, usually concentric. Heart disease in affected females tends to be clinically recognized later than in males and cardiac complications are the most frequently reported cause of death in females with Fabry disease. There are few data regarding the association between Fabry disease and LV noncompaction. We report a case of a 30-year-old asymptomatic woman, heterozygous for a nonsense alpha-galactosidase gene mutation (p.R220X), who presented LV noncompaction on cardiac magnetic resonance imaging, without LV wall hypertrophy. Histopathological examination of myocardial fragments showed marked deposition of glycosphingolipids in cardiomyocytes, confirming the diagnosis of Fabry cardiomyopathy. Based on this finding, the patient was proposed for enzyme replacement therapy. This case illustrates the role of endomyocardial biopsy in the clarification of doubtful or atypical findings related to cardiac Fabry disease, even in heterozygous women, and corroborates the contention that Fabry disease should be included in the differential diagnosis of LV hypertrabeculation/noncompaction.

Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis.

Kufs disease, an adult-onset neuronal ceroid lipofuscinosis, is challenging to diagnose and genetically heterogeneous. Mutations in CLN6 were recently identified in recessive Kufs disease presenting as progressive myoclonus epilepsy (Type A), whereas the molecular basis of cases presenting with dementia and motor features (Type B) is unknown. We performed genome-wide linkage mapping of two families with recessive Type B Kufs disease and identified a single region on chromosome 11 to which both families showed linkage. Exome sequencing of five samples from the two families identified homozygous and compound heterozygous missense mutations in CTSF within this linkage region. We subsequently sequenced CTSF in 22 unrelated individuals with suspected recessive Kufs disease, and identified an additional patient with compound heterozygous mutations. CTSF encodes cathepsin F, a lysosomal cysteine protease, dysfunction of which is a highly plausible candidate mechanism for a storage disorder like ceroid lipofuscinosis. In silico modeling suggested the missense mutations would alter protein structure and function. Moreover, re-examination of a previously published mouse knockout of Ctsf shows that it recapitulates the light and electron-microscopic pathological features of Kufs disease. Although CTSF mutations account for a minority of cases of type B Kufs, CTSF screening should be considered in cases with early-onset dementia and may avoid the need for invasive biopsies.

Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.

We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and 2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs∗10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.

A novel type of familial proximal axonal dystrophy: three cases and a review of the axonal dystrophies.

Three related infants of Roma ancestry, two of them siblings, showed hypotonia, predominantly axial, from birth, difficulty swallowing, myoclonic seizures, and respiratory difficulty. Dysmorphic features, principally micrognathia were present. EEGs showed focal epileptiform abnormalities. All three died in their 5th month from respiratory insufficiency complicated by pneumonia. Autopsy showed small brains without malformation. Microscopy revealed numerous axonal spheroids involving particularly the brain stem and spinal cord, with especial prominence in the middle cerebellar peduncle, the anterior part of the thalamic reticular nuclei, and the anterior horns and columns of the spinal cord. Spheroids that appeared to be on axons of lower motor neurons were especially large. No spheroids were seen in peripheral nerves; electron microscopy did not show spheroids in skin. By electron microscopy spheroids contained neurofilaments, sparse mitochondria, and electron dense granules. The material did not allow identification of microtubules. Closely packed vesicles excluded neurofilamanets from the center of many spheroids, especially in the middle cerebellar peduncle. Sprouting of axons from the surface of many spheroids was seen. This disease is distinct from the well described type of infantile neuroaxonal dystrophy (Seitelberger's disease) in view of the distribution of spheroids, presence of spheroids on proximal rather than distal parts of axons, sparing of the peripheral nerves, lack of staining for synuclein, presence of sprouting, and lack of membranous profiles in the spheroids. A review of reported types of axonal dystrophy has not shown identical cases.

Adult-onset leukodystrophy with axonal spheroids.

We report two cases of adult-onset leukodystrophy with axonal spheroids in a brother and sister, one with an autopsy, the other with a cerebral biopsy. Symptoms developed at 24 and 33years. The sister died within four years, her brother in 2 and a half. Her brain showed a large lesion in the frontal centrum semiovale extending through the corpus callosum and shading off into the normal appearing U-fibers. With routine stains axonal spheroids were most easily detected in the mildly affected regions, although stains for neurofilaments showed that they were actually more numerous, though more irregular in shape, where the lesions were more severe. Axons and myelin appeared equally affected. Pigmented cells were absent. Electron microscopy on the cerebral biopsy showed that the spheroids contained neurofilaments and neurotubules, mitochondria and degenerate mitochondria, with a suggestion of polarity such that neurofilaments were more common in the proximal part of spheroids. Many other axons were found whose size was only slightly increased although they were filled with sacs of abnormal granular material which were probably derived from mitochondria. The anterior commissure and the corticospinal tracts in the spinal cord of the sister showed fiber loss and large vacuoles within which occasional intact axons could be identified. This was considered to represent intramyelin edema. In the cerebral biopsy one vacuole arising from myelin splitting was found in confirmation of this hypothesis. We conclude that both myelin and axons are damaged, although the lesions of myelin are conditioned by axonal abnormalies in this genetic disease.

Sporadic Creutzfeldt-Jakob disease causing a 2-years slowly progressive isolated dementia.

A 47-year-old woman was seen for progressive behavioural and cognitive disturbances slowly evolving over a 1-year period. Neuropsychological evaluation disclosed moderate to severe impairment of all cortical functions. Besides this no other clinical abnormality was found. MRI diffusion weighted imaging disclosed hyperintense cortical lesions in a ribbon-like fashion, with restricted diffusivity. EEG showed no periodic sharp waves and CSF examination was normal, including protein 14.3.3. She was heterozygote on codon 129. Her cognitive function continued to decline and she was readmitted for further investigation at the 24th month of disease. Again no ataxia or involuntary movements were observed. MRI disclosed widespread hyperintense lesions over the entire cortex and, for the first time, also caudato-putaminal hyperintensity in T2-weighted images. EEG again failed to show periodic activity. Stereotactic biopsy disclosed moderate spongiform changes, astrocytosis and perivacuolar staining with prion-directed antibodies. Western blot analysis revealed prion type 2 mobility pattern. We discuss the clinical significance of this case: as dementia was the sole finding, and this was slowly-evolving over a 2-year period, MRI findings were the key factor suggesting a prion disease in a woman that otherwise would probably be diagnosed with a primary degenerative dementia.

SANDO: two novel mutations in POLG1 gene.

Sensory ataxia with neuropathy, dysarthria and ophthalmoparesis represent the clinical triad of SANDO, a specific mitochondrial phenotype first reported in 1997 in association with multiple mitochondrial DNA deletions and mutations in POLG1 or more rarely in the C10orf2 (twinkle-helicase) gene. We report a 44-year-old man with SANDO who harboured two novel mutations (P648R/R807C) in the POLG1 gene.

Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder.

Action myoclonus-renal failure syndrome (AMRF) is a distinctive form of progressive myoclonus epilepsy associated with renal dysfunction. The syndrome was not recognized prior to the advent of dialysis and renal transplantation because of its rapidly fatal course if renal failure is untreated. The first and only description of AMRF was in four French Canadian patients in three families (Andermann et al., 1986). We now describe 15 individuals with AMRF from five countries, including a follow-up of the four French Canadian patients, allowing a more complete characterization of this disease. Our 15 patients with AMRF belong to nine different families. Segregation analyses were compatible with autosomal recessive inheritance. In addition, our findings show that AMRF can present with either renal or neurological features. Tremor (onset 17-26 years, mean 19.8 years, median 19 years) and progressively disabling action myoclonus (onset 14-29 years, mean 21.7 years, median 21 years), with infrequent generalized seizures (onset 20-28 years, mean 22.7 years, median 22 years) and cerebellar features are characteristic. Proteinuria, detected between ages 9 and 30 years in all cases, progressed to renal failure in 12 out of 15 patients within 0-8 years after proteinuria detection. Brain autopsy in two patients revealed extraneuronal pigment accumulation. Renal biopsies showed collapsing glomerulopathy, a severe variant of focal glomerulosclerosis. This study extends the AMRF phenotype, and demonstrates a more extensive ethnic and geographic distribution of a syndrome originally believed to be confined to individuals of French Canadian ancestry. The independent progression of neurological and renal disorders in AMRF suggests a unitary molecular lesion with pleiotropic effects. Our results demonstrate that the renal lesion in AMRF is a recessive form of collapsing glomerulopathy. Genes identified for focal segmental glomerulosclerosis and involved with the function of the glomerular basement membrane and related proteins are thus good candidates. Treatment can improve quality of life and extend the lifespan of these patients. Dialysis and renal transplantation are effective for the renal but not the neurological features, which continue to progress even in the presence of normalized renal function; the latter can be managed with anti-myoclonic and anti-epileptic drugs.

Simulation of brain death from fulminant de-efferentation.

BACKGROUND: Guillain-Barré syndrome (GBS) classically presents with a subacutely evolving areflexic paralysis, with typical laboratory findings of elevated cerebrospinal fluid protein and abnormal nerve conduction studies. There is now an increasing recognition of GBS variants that differ in clinical presentation, prognosis, electrophysiology and presumed pathogenesis. Fulminant cases of GBS have been reported in which a rapid deterioration evolves to a clinical state resembling "brain death". METHODS: A retrospective analysis of two such cases of fulminant neuropathy are described, that includes the clinical course, electrophysiology and neuropathology where available. RESULTS: We describe two patients that presented with a rapid course of neurological deterioration, lapsing into what resembled a "clinically brain-dead" state that was subsequently ascribed to a fulminant polyneuropathy. Investigations (electrophysiological, pathological) and the clinical course suggested an axonal neuropathy. CONCLUSIONS: A fulminant neuropathy can result in a clinical state resembling "brain death" through diffuse de-efferentation. Although generally attributed to aggressive demyelination with secondary axonal degeneration, a primary axonopathy can also lead to a similar clinical presentation.

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum.

Hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (OMIM 218000) is an autosomal recessive disease of early onset characterized by a delay in developmental milestones, a severe sensory-motor polyneuropathy with areflexia, a variable degree of agenesis of the corpus callosum, amyotrophy, hypotonia, and cognitive impairment. Although this disorder has rarely been reported worldwide, it has a high prevalence in the Saguenay-Lac-St-Jean region of the province of Quebec (Canada) predominantly because of a founder effect. The gene defect responsible for this disorder recently has been identified, and it is a protein-truncating mutation in the SLC12A6 gene, which codes for a cotransporter protein known as KCC3. Herein, we provide the first extensive review of this disorder, covering epidemiological, clinical, and molecular genetic studies.