Dyslipidemia and hypercalciuria in a patient with pantothenate kinase 2 deficiency: A novel variant and case report.

Pantothenate kinase-associated neurodegeneration (PKAN, OMIM: 234200) results from biallelic pathogenic variants in PANK2 which encodes pantothenate kinase 2, a crucial mitochondrial enzyme involved in coenzyme A biosynthesis. Pantothenate kinase-associated neurodegeneration patients typically exhibit the distinctive "eye of the tiger" sign on brain magnetic resonance imaging in the globus pallidus, along with psychiatric symptoms, extrapyramidal movements such as parkinsonism and dystonia, eventual speech and gait impairments, and the presence of dysphagia. An 11-year-old girl, with fifth-degree consanguinity, demonstrated typical psychomotor development and growth until the age of 5, when she began experiencing psychiatric symptoms. At the age of 9, she developed hand tremors, progressing to generalized muscular dystonia. By age 10, she exhibited gait and speech impairment. Physical examination revealed extensive generalized dystonia, hand tremors, speech impairment, dysphagia, inability to walk, and heightened osteotendinous reflexes. Metabolic analysis identified dyslipidemia with partial response to statin treatment and normocalcemic hypercalciuria. Exome sequencing revealed a novel likely pathogenic variant in PANK2 (NM_001386393.1:c.526C > G) in a homozygotic state. Pantothenate kinase-associated neurodegeneration typically manifests with generalized dystonia and psychiatric symptoms. Here, we present a Pantothenate kinase-associated neurodegeneration patient with dyslipidemia and hypercalciuria as potentially previously undescribed metabolic phenotype.

Type 1 neurodegeneration with brain iron accumulation: a case report.

BACKGROUND: Type 1 neurodegeneration with brain iron accumulation is a rare neurological disorder with estimated prevalence of one to two per million persons worldwide, characterized by progressive degeneration of basal ganglia, globus pallidus, and reticular part of substantia nigra, produced by brain iron accumulation due to a defect in the gene producing pantothenate kinase 2. Clinical presentations include dystonia, dysarthria, dysphagia, dementia, severe mental retardation, and severe movement disability at later stages. The characteristic pattern on brain magnetic resonance imaging shows the "eye of the tiger" sign. Treatment in late stages is mainly symptomatic. We report the case of a Cuban boy with high-severity brain iron accumulation, with positive clinical and imaging findings diagnosed in a late stage of the illness. This degree of severity has never been reported in Cuba and is rarely reported worldwide. CASE PRESENTATION: We present the case of a 19-year-old male white Cuban boy who presented to our department with features of spasticity, dystonia, gait difficulty, dysarthria, dysphagia, aggressiveness, and sleep disorders. He was diagnosed with pantothenate kinase-associated neurodegeneration on the basis of clinical findings and typical "eye of the tiger" pattern on brain magnetic resonance imaging. Detailed evaluation was carried out, and symptomatic treatment and physiotherapy were started with trihexyphenidyl, cabergoline, baclofen, and intramuscular botulinum neurotoxin as well as daily home sessions of passive stretching, weight bearing, and muscle massaging. At 3 months reevaluation, the patient showed a great improvement of motor function, with a decrease of dystonic symptoms, although language, cognition, and functional independence showed no improvement. The prognosis of the patient remains reserved. CONCLUSION: The diagnosis can be made based on the presence of clinical and imaging features. The presence of "eye-of-the-tiger" sign on magnetic resonance imaging must be considered a nearly pathognomonic sign of neurodegeneration with brain iron accumulation presence. Treatment after high-severity presentation remains directed toward symptomatic findings. Both dopamine agonists and anticholinergic agents are useful to treat motor symptoms, but there is not yet an effective treatment to stop the underlying degeneration. New therapeutic approaches are needed to counteract late stages of the disease and improve prognosis.

Cerebral and cerebellar white matter tract alterations in patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN).

BACKGROUND: To examine structural connectivity of white matter tracts in patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN) dystonia and identify those ones which correlate negatively to severity of symptoms. METHODS: In a group of 41 patients suffering from PKAN dystonia and an age- and gender-matched control group, white matter tractography was carried out, based on diffusion tensor imaging magnetic resonance data. Postprocessing included assessment of Quantitative Anisotropy (QA) using q-space diffeomorphic reconstruction in order to reduce influence of iron accumulation in globus pallidus of patients. RESULTS: Whole brain tractography presented significantly reduced QA values in patients (0.282 ± 0.056, as compared to controls (0.325 ± 0.046, p < 0.001). 9 fiber clusters of tracts correlated negatively to the dystonia score of patients: the middle cerebellar peduncle and the tracts of both cerebellar hemispheres as well as corpus callosum, forceps minor, the superior cortico-striate tracts and the superior thalamic radiations of both cerebral hemispheres (False Discovery Rate FDR = 0.041). CONCLUSION: The finding of a reduced global structural connectivity within the white matter and of negative correlation of motor system-related tracts, mainly those between the basal ganglia, cortical areas and the cerebellum, fits well to the concept of a general functional disturbance of the motor system in PKAN.

Changes in Cerebral Gray and White Matter in Patients with Pantothenate Kinase-Associated Neurodegeneration: A Long-Term Magnetic Resonance Imaging Follow-Up Study.

OBJECTIVE: To determine the volume changes in gray and white matter during a long-term follow-up in patients suffering from pantothenate kinase-associated neurodegeneration (PKAN). METHODS: Magnetic resonance imaging was repeated in 13 patients and 14 age-matched controls after a mean interval of more than 7 years. T1-weighted sequences were evaluated by fully automated atlas-based volumetry, compared between groups and correlated with disease progression. RESULTS: The patients did not show generalized cerebral atrophy but did show a significantly faster volume reduction in the globus pallidus during follow-up (between -0.96% and -1.02% per year, p < 0.05 adjusted for false discovery rate) than controls, which was significantly related to the progression in their dystonia scores (p = 0.032). CONCLUSION: The volume loss in the globus pallidus over time-together with the accumulation of iron known as the "tiger's eye"-supports the pathophysiologic concept of this nucleus as a center of inhibition and its severe malfunction in PKAN.

Functional connectivity of the motor system in dystonia due to PKAN.

PURPOSE: To demonstrate deviations of functional connectivity within the motor system in dystonic patients suffering from Pantothenate Kinase Associated Neurodegeneration, a genetic and metabolic disease, which is characterized by a primary lesion in the globus pallidus. MATERIAL AND METHODS: Functional Magnetic Resonance Imaging data were measured during resting state in 12 patients suffering from a confirmed mutation of the PANK2 gene. In this region-of-interest based analysis, data were evaluated in respect to correlation of signal time course between basal ganglia, motor-related cortical regions and cerebellum, were related to clinical data and were compared to a control group of 20 healthy volunteers. RESULTS: During resting state, correlation coefficients within the motor system were significantly lower in patients than in controls (0.025 vs. 0.133, p < 0.05). Network analysis by Network Based Statistics showed that these differences mainly affected the connectivity between a sub-network consisting of the basal ganglia and another one, the motor system-related cortical areas (p < 0.05). 6 out of 12 connections, which correlated significantly to duration of disease, were connections between both sub-networks. CONCLUSION: The finding of a reduced functional connectivity within the motor network, between the basal ganglia and cortical motor-related areas, fits well into the concept of a general functional disturbance of the motor system in PKAN.

Cerebral blood flow in dystonia due to pantothenate kinase-associated neurodegeneration.

BACKGROUND AND PURPOSE: The aim of this study was to look for deviations of cerebral perfusion in patients suffering from pantothenate kinase-associated neurodegeneration, where the globus pallidus is affected by severe accumulation of iron. MATERIAL AND METHODS: Under resting conditions, cerebral blood flow was measured by the magnetic resonance imaging technique of arterial spin labelling in cortical areas and basal ganglia in eight pantothenate kinase-associated neurodegeneration patients and 14 healthy age-matched control subjects and correlated to T2* time of these areas and - in patients - to clinical parameters. RESULTS: Despite highly significant differences of T2* time of the globus pallidus (20 vs 39 ms, p < 0.001), perfusion values of this nucleus were nearly identical in both groups (32 ± 3.3 vs 31 ± 4.0 ml/min/100 g) as well as in total brain gray matter (both 62 ± 6.7 resp. ±10.3 ml/min/100 g), putamen (41 ± 5.4 vs 40 ± 6.1 ml/min/100 g), in selected cortical regions, and the cerebellum. Correlations between perfusion and T2* time to clinical data did not reach significance (p > 0.05). CONCLUSION: The absence of any obvious deviations of perfusion in the group of patients during a resting condition does not support the view that (non-functional) vascular pathology is a major pathogenic factor in pantothenate kinase-associated neurodegeneration in the younger age group. The findings underline the value of the arterial spin technique to measure cerebral blood flow in areas of disturbed susceptibility.

All that glitters is not gold: When motor and vocal tics in a child do not match Tourette syndrome: A case report / Nem tudo que reluz é ouro: quando tiques motores e vocais em uma criança não combinam com Síndrome de Tourette: relato de caso

ABSTRACT The atypical form of Pantothenate Kinase-Associated Neurodegeneration (PKAN) tends to present at around the age of 14 years, has a heterogeneous presentation with extrapyramidal symptoms, and approximately one third of patients exhibit psychiatric problems. This paper reports the case of a patient with apparent typical symptoms of Tourette syndrome. However, the severity and poor response to treatment led to further investigation and the diagnosis of PKAN as a secondary cause of Tourettism was reached.

RESUMO A forma atípica de PKAN costuma se apresentar por volta dos 14 anos de idade, possui uma sintomatologia heterogênea, com sintomas extrapiramidais e, em cerca de um terço dos pacientes, também com a manifestação de sintomas psiquiátricos. O presente artigo relata o caso de uma paciente com sintomatologia típica da Síndrome de Tourette à primeira vista. Entretanto, a gravidade do quadro e pouca resposta ao tratamento levaram a uma maior investigação e ao diagnóstico de PKAN como causa secundária do Tourettismo.

All that glitters is not gold: When motor and vocal tics in a child do not match Tourette syndrome: A case report.

The atypical form of Pantothenate Kinase-Associated Neurodegeneration (PKAN) tends to present at around the age of 14 years, has a heterogeneous presentation with extrapyramidal symptoms, and approximately one third of patients exhibit psychiatric problems. This paper reports the case of a patient with apparent typical symptoms of Tourette syndrome. However, the severity and poor response to treatment led to further investigation and the diagnosis of PKAN as a secondary cause of Tourettism was reached.

A forma atípica de PKAN costuma se apresentar por volta dos 14 anos de idade, possui uma sintomatologia heterogênea, com sintomas extrapiramidais e, em cerca de um terço dos pacientes, também com a manifestação de sintomas psiquiátricos. O presente artigo relata o caso de uma paciente com sintomatologia típica da Síndrome de Tourette à primeira vista. Entretanto, a gravidade do quadro e pouca resposta ao tratamento levaram a uma maior investigação e ao diagnóstico de PKAN como causa secundária do Tourettismo.

Déficit de pantotenato quinasa asociado a neurodegeneración: reporte de un caso clásico y revisión de la literatura / Pantothenate kinase-associated neurodegeneration: a classical case report and literature review

El déficit de pantotenato quinasa asociado a neurodegeneración (PKAN por su sigla en inglés) es una enfermedadneurodegenerativa poco frecuente que se caracteriza por disfunción extrapiramidal progresiva y acumulaciónde hierro en los ganglios basales. El signo clásico en la neuroimagen de “ojos de tigre” se ve en las imágenesponderadas en T2 en la resonancia magnética cerebral. A continuación presentamos un caso clásico de la enfermedaden un niño que inicia con síntomas motores a los 5 años de edad y que fue estudiado en el Instituto deOrtopedia Infantil Roosevelt, con neuroimágenes típicas y confirmación de la mutación por estudio molecular.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare neurodegenerative disease characterized by progressive extrapyramidal dysfunction and iron accumulation in the basal ganglia. The classic sign in neuroimaging of "eye of the tiger" is seen on T2-weighted magnetic resonance imaging scan. We present a classic case of the disease in a child who starts with motor symptoms at 5 years old and was studied at the Instituto de Ortopedia Infantil Roosevelt, with typical neuroimaging and confirmation of the mutation by molecular study.

Presentación clínica típica y atípica de déficit de pantotenato quinasa, reporte de 2 casos / Typical and atypical presentation pantothenate kinase deficiency: reports of two cases and a review of current literature

Los síndromes de neurodegeneración asociada al hierro son una causa secundaria importante de extrapiramidalismo (1). De aparición entre los 6 y 40 años, se asocian además a cambios comportamentales y demencia (2). La base fisiopatológica son los depósitos de hierro a nivel ganglio basal. De estas enfermedades, la más frecuente es el déficit de pantotenato quinasa (PKAN por su siglas en inglés), constituyendo más del 50% de los casos de esta enfermedad. Se han descrito 2 formas de presentación típica o temprana, y atípica o tardía2. Se reportan a continuación dos casos: uno de presentación típica y otro de presentación atípica, diagnosticados en el hospital San Ignacio de Bogotá, Colombia.

Neurodegenerations associated with iron deposites are an important secondary cause extrapiramidalism. Their onsets are between 6 and 40 years, and are associated with behavioral changes and dementia. The pathophysiological bases are iron deposits at the basal ganglia. Of these diseases, the most frequent is Pantothenate kinase associated neurodegeneration (PKAN by its acronym), which constitutes over 50% of cases of the disease. Two forms of presentation have been described: typical (early onset) and atypical (late onset). We report two cases in the following: one typical and one atypical presentation, both diagnosed in San Ignacio Hospital in Bogotá, Colombia.

Neuropareidolia: diagnostic clues apropos of visual illusions / Neuropareidolia: pista diagnóstica a partir de uma ilusão visual

Diagnosis in neuroimaging involves the recognition of specific patterns indicative of particular diseases. Pareidolia, the misperception of vague or obscure stimuli being perceived as something clear and distinct, is somewhat beneficial for the physician in the pursuit of diagnostic strategies. Animals may be pareidolically recognized in neuroimages according to the presence of specific diseases. By associating a given radiological aspect with an animal, doctors improve their diagnostic skills and reinforce mnemonic strategies in radiology practice. The most important pareidolical perceptions of animals in neuroimaging are the hummingbird sign in progressive supranuclear palsy, the panda sign in Wilson's disease, the panda sign in sarcoidosis, the butterfly sign in glioblastomas, the butterfly sign in progressive scoliosis and horizontal gaze palsy, the elephant sign in Alzheimer's disease and the eye-of-the-tiger sign in pantothenate kinase-associated neurodegenerative disease.

O diagnóstico em neuroimagem envolve o reconhecimento de padrões específicos indicativos de doenças particulares. Pareidolia, é a perceção equivocada de algo claro e distinto a partir de um estímulo vago e obscuro, por vezes benéfico a quem interpreta exames de imagem na procura do diagnóstico. A este propósito, alguns animais podem pareidolicamente ser reconhecidos em neuroimagens associadas a determinadas doenças específicas, promovendo mais rapidez na habilidade diagnóstica e naturalmente reforçando estratégias mnemônicas individuais na prática do diagnóstico neuroradiológico. Alguns dos sinais de neuroimagens relacionados a percepções pareidolicas de animais são: o sinal do beja-flor na paralisia supra nuclear progressiva; o sinal do panda na doença de Wilson; o sinal do panda na sarcoisdose; o sinal da borboleta no glioblastoma; o sinal da borboleta no escoliose progressiva e paralisia do olhar horizontal; o sinal do elefante na doença de Alzheimeir; e o sinal do olho de tigre na doença degenerativa ligada a pantothenato kinase.