Progressive myoclonus epilepsy and ceroidolipofuscinosis 14: The multifaceted phenotypic spectrum of KCTD7-related disorders.

BACKGROUND: Mutations in the KCTD7 gene have been associated with progressive myoclonus epilepsy and, in a single patient, with the so-called "Neuronal Ceroid Lipofuscinosis 14" (characterised by myoclonic seizures, cognitive regression, optic atrophy leading to visual loss, and progressive cortical and cerebellar atrophy). CLINICAL REPORTS: We describe two new patients carrying two novel pathogenic mutations in the KCTD7 gene. Patient 1 (NM_153033.4: c.[533C > T], NP_694578: p.[(Ala178Val)]) was a 17-year-old girl who presented with early-onset epilepsy resembling epilepsia partialis continua (responsive to intravenous corticosteroids and immunoglobulins), and later developed myoclonic seizures and atypical absences, photosensitivity to very low frequencies and progressive seizures-related neurocognitive and motor deterioration. Patient 2 (NM_153033.4: c.[172G>A], NP_694578: p.[(Gly58Arg)]) presented with early neurological regression, myoclonic seizures and lysosomal storage material which was consistent with a neuronal ceroid lipofuscinosis (NCL) at skin biopsy. Both patients had non epileptic myoclonus. CONCLUSIONS: The two reported patients carrying novel pathogenic variants in KCTD7 gene presented with a remarkable phenotypic heterogeneity including: a) progressive myoclonus epilepsy without NCL-type lysosomal storages; b) progressive myoclonus epilepsy with lysosomal storages resembling NCL pattern (NCL14); c) progressive myoclonus epilepsy with epilepsia partialis continua.

Longitudinal In Vivo Monitoring of the CNS Demonstrates the Efficacy of Gene Therapy in a Sheep Model of CLN5 Batten Disease.

Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are neurodegenerative lysosomal storage diseases predominantly affecting children. Single administration of brain-directed lentiviral or recombinant single-stranded adeno-associated virus 9 (ssAAV9) vectors expressing ovine CLN5 into six pre-clinically affected sheep with a naturally occurring CLN5 NCL resulted in long-term disease attenuation. Treatment efficacy was demonstrated by non-invasive longitudinal in vivo monitoring developed to align with assessments used in human medicine. The treated sheep retained neurological and cognitive function, and one ssAAV9-treated animal has been retained and is now 57 months old, almost triple the lifespan of untreated CLN5-affected sheep. The onset of visual deficits was much delayed. Computed tomography and MRI showed that brain structures and volumes remained stable. Because gene therapy in humans is more likely to begin after clinical diagnosis, self-complementary AAV9-CLN5 was injected into the brain ventricles of four 7-month-old affected sheep already showing early clinical signs in a second trial. This also halted disease progression beyond their natural lifespan. These findings demonstrate the efficacy of CLN5 gene therapy, using three different vector platforms, in a large animal model and, thus, the prognosis for human translation.

MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis.

BACKGROUND AND PURPOSE: Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase 1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood death. As part of a project studying the treatment benefits of a combination of cysteamine bitartrate and N-acetyl cysteine, we made serial measurements of patients' brain volumes with MR imaging. MATERIALS AND METHODS: Ten patients with infantile neuronal ceroid lipofuscinosis participating in a treatment/follow-up study underwent brain MR imaging that included high-resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brain stem, and thalamus. Patients' brain volumes were compared with those of a healthy population. RESULTS: Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss and may never have been normal postnatally. The thalamus dropped out of the normal range around 6 months of age; the cerebellum, around 2 years of age; and the brain stem, around 3 years of age. CONCLUSIONS: Rapid cerebral volume loss was expected on the basis of previous qualitative reports. Because our study did not include a nontreatment arm and because progression of brain volumes in infantile neuronal ceroid lipofuscinosis has not been previously quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions.

[Neuronal ceroid lipofuscinosis: clinical and neuroradiological findings]. / Lipofuscinose ceróide neuronal: achados clínicos e neurorradiológicos.

The neuronal ceroid lipofuscinoses (NCL) are a group of neurodegenerative disorders, characterized by abnormal storage of an autofluorescent substance of lipopigments, resembling ceroid and lipofuscin, within lysosomes of neurons and other types of cells. The main phenotypic subtypes have been established on the basis of age of onset, clinical course, and ultra structural morphology, and classified as infantile, late infantile, juvenile and adult forms. Six genes have been associated with human NCL and approximately 150 mutations have been described. The aim of this study is to report the clinical, neuroradiological, and morphological characteristics of seven patients evaluated at Sarah Network of Hospitals for Reabilitation-Fortaleza-Ceará-Brazil. Five cases were histopathologically confirmed with skin biopsy and two were siblings of confirmed patients. An early diagnosis of NCL, an autosomal recessive disease, is mandatory for genetic counseling and to avoid further cases in the family. Imaging findings can contribute to the differential diagnosis.

Autosomal dominant adult neuronal ceroid lipofuscinosis: parkinsonism due to both striatal and nigral dysfunction.

We describe a family with adult neuronal ceroid lipofuscinosis, with apparent autosomal dominant inheritance, observed in six affected individuals in three generations. Disease onset was usually in the fifth decade, but was earlier in the youngest generation. Early symptoms consisted of myoclonus in face and arms, epilepsy, auditory symptoms, cognitive decline, or depression. Parkinsonism occurred a few years after disease onset, with stooped posture, shuffling gait, bradykinesia, and mask face. Four subjects deteriorated to a state of severe handicap, with severe dementia, contractures, dysphagia, and dysarthria. Leg weakness evolved to flaccid paraparesis in two patients. Diagnosis was confirmed by brain biopsy in one patient and full autopsy in two patients. Abundant intraneuronal storage of autofluorescent material was found throughout the brain. Electron microscopy showed granular osmiophilic deposits and scarce fingerprint profiles. Striking loss of neurons in the substantia nigra pars compacta and reticulata was found. (123)I-IBZM Single photon emission computed tomography in two patients showed loss of postsynaptic D2 receptor binding in the striatum. We conclude that parkinsonism in ANCL is likely to be caused by both presynaptic nigral cell loss and postsynaptic striatal degeneration.

Impaired temporo-occipital blood flow in an atypical CLN1 case with late infantile onset and granular osmiophilic deposits.

A 5-year-old boy presented with frequent absences. Speech began to regress. He became ataxic, barely able to walk. Studies with Xe-133 and hexamethylpropylene amine oxime single-photon emission computed tomography revealed sharply decreased cerebral blood flow, especially in the occipital area. Landau-Kleffner syndrome was suspected but a sleep electroencephalogram showed few abnormalities. He was started on clorazepate and diltiazem. A skin biopsy to rule out possible CLN2 revealed, instead of the predicted curvilinear profiles, granular osmiophilic deposits, consistent with infantile neuronal ceroid lipofuscinosis (CLN1). The family reported increased seizure frequency and consulted with a colleague, who advised them to resume valproate and discontinue diltiazem. The boy died shortly thereafter. Decreased cerebral blood flow is a new finding in CLN1 with delayed onset. Calcium-channel blockers improve cerebral blood flow and perhaps delay clinical regression.

[Kufs-disease; a rare cause of early-onset dementia]. / Die Kufs-Erkrankung. Seltene Ursache einer früh beginnenden Demenz.

The case of a 35-year-old man with progressive dementia from the age of 17 is presented. Clinical examination showed mild extrapyramidal and cerebellar signs and rare myoclonus. Neuropsychological evaluation disclosed severe cognitive deficits. Magnetic resonance imaging (MRI) revealed moderate generalized atrophy with abnormal iron deposition in the basal ganglia. Positron emission tomography (PET) with 18-fluorodeoxyglucose (18-FDG) demonstrated clear temporoparietal hypometabolism. The clinical symptoms and course are typical for the rare adult type of neuronal ceroid lipofuscinoses (Kufs' disease). The diagnosis is supported by the electron microscope detection of an abnormal accumulation of lipid vacuoles and lipofuscin in the eccrine sweat glands and the rectal ganglia cells.

Adult neuronal ceroid lipofuscinosis (Kufs' disease) in two siblings of an Irish family.

The clinico-pathologic features of two siblings with biopsy-proven adult onset neuronal ceroid lipofuscinosis (Kufs' disease) are described. A 38-year-old woman had intractable seizures, delusions and hallucinations followed by ataxia, declining cognitive function and death. At autopsy there was widespread cerebral neuronal accumulation of autofluorescent pigment, in which fingerprint profiles were demonstrated. Systemic involvement was not demonstrated. A 43-year-old brother developed slowly progressive cerebellar ataxia and was found to have similar neuronal autofluorescent pigment on brain biopsy. Nine years later there is gradual cognitive decline and profound ataxia. The salient features of Kufs' disease including cases published since 1988 are reviewed.

[MRI and computer-assisted tomography in Kufs disease. Apropos of a familial form]. / IRM et scanographie de la maladie de Kufs. A propos d'une forme familiale.

Kufs disease is the adult form of ceroid neurolipofuscinosis, and an uncommon cause of degenerative nervous system disease affecting young adults. We present here 4 cases of family form revealed by a demential syndrome. In all 4 patients MRI showed diffuse cortical atrophy predominant in the parietal regions. In 3 of these 4 patients MRI also exhibited a low signal in T2-weighted sequences on the putamens. There was no abnormality of the white matter. Diagnosis was made by cerebral biopsy in one case and by rectal biopsy in all other cases. Although the MRI images are not specific, they must be used when the diagnosis of Kufs disease is suspected in young patients with demential syndrome.

[Kufs disease with leukoencephalopathy]. / Maladie de Kufs avec leucoencéphalopathie.

We report a case of adult neuronal ceroid lipofuscinosis (Kufs' disease) with leukoencephalopathy on cerebral scan CT and MRI. A 52 year-old woman presented with partial complex epileptic seizure followed by progressive dementia, cerebellar ataxia, pyramidal and akineto-rigid signs and symptoms. After 6 years of evolution, cerebral stereotactic biopsies showed a diffuse gliosis of the white matter, but no clear demyelination. Nerve and glial cells contained numerous PAS+ autofluorescent granules. In the oligodendrocytes and astrocytes of the white matter these granules appeared electronmicroscopically as cytoplasmic osmiophilic lamellar bodies with fingerprint profile combined with some curvilinear and rectilinear aspects. The cortical nerve cells contained granular osmiophilic bodies. This "leukoencephalopathic" variant of Kufs' disease is probably related to the pigmentary type of orthochromatic leukodystrophy, wherein similar inclusions have been only described in the macrophages and glial cells of the white matter.

Positron emission tomography in neuronal ceroid lipofuscinosis (Jansky-Bielschowsky disease): a case report.

We report on a 13-year-old girl with late infantile neuronal ceroid lipofuscinosis (NCL) in whom PET scanning with [18F]-2-fluoro-2-deoxy-D-glucose ([18F]/FDG) was performed. Early psychomotor development was normal. At the age of 2 years, neurological signs such as hypotonia and incoordination appeared, followed by visual failure and ataxia. At the age of 4, funduscopic examination showed macular degeneration and papillary atrophy. At the age of 9, myoclonic jerks were observed; subsequently, generalized seizures together with failing vision, mental deterioration, and visual and auditory hallucinations appeared. Brain MRI showed severe cortical and subcortical atrophy. A skin biopsy detected the presence of 'finger-print' inclusions in the cytoplasm of smooth muscle fibers. Late infantile NCL (Jansky-Bielschowsky disease) was diagnosed. FDG/PET revealed a severe reduction of metabolism in all the cortical and subcortical structures. A regional analysis of the distribution of the tracer revealed marked bilateral hypometabolism, particularly in calcarine, lateral, occipital, and temporal cortices and in the thalamus.

Early differential diagnosis of infantile neuronal ceroid lipofuscinosis, Rett syndrome, and Krabbe disease by CT and MR.

PURPOSE: To compare early radiologic findings in three clinically similar progressive encephalopathies of childhood. METHODS: Brain CT and/or MR studies were done in 57 children 3 to 36 months of age: 16 with infantile neuronal ceroid lipofuscinosis, 5 with Rett syndrome, 6 with Krabbe disease, and 30 control subjects with normal neurologic status. In addition, previous descriptions in the literature were collected. RESULTS: No significant changes were seen in Rett syndrome. Early atrophy was found in infantile neuronal ceroid lipofuscinosis and in Krabbe disease, being more severe in the latter. The thalami were hyperdense in 4 of 13 patients with infantile neuronal ceroid lipofuscinosis and in 1 of 4 patients with Krabbe disease (in the literature in 12 of 30 examinations). Cerebral calcifications and density abnormalities in the cerebral and cerebellar white matter were seen in Krabbe disease only. On MR, the white matter changes in the two diseases were differently located. In every patient with infantile neuronal ceroid lipofuscinosis, decreased T2 signal was seen in the thalami and periventricular high-signal rims after the age of 13 months. Hypointensity of the thalami and basal ganglia was seen in both diseases, but Krabbe disease showed more variations. Abnormalities of cerebellar intensity were found in Krabbe disease only. CONCLUSIONS: CT and MR are of value in the differential diagnosis of these three diseases. MR especially facilitates the early diagnosis of infantile neuronal ceroid lipofuscinosis.

CT in ceroid lipofuscinosis.

The diagnosis of the childhood forms of neuronal ceroid lipofuscinosis is considered when a child presents with seizures, dementia, and pigmentary change in the retina. A diagnosis is based on the result of skin or conjunctival biopsy. We report two children who had CTs obtained at the onset of seizures and prior to the occurrence of intellectual deterioration or retinal pigmentary changes. In both cases, the CT showed marked enlargement of the fourth ventricle and cerebellar atrophy without concomitant cerebral atrophy. We suggest that this cerebellar atrophy may be an early sign of ceroid lipofuscinosis and may be of particular note when seen on the CT scan of a child with a recent onset of seizures.