Botulinum toxin injection to improve functional independence and to alleviate parenting stress in a child with advanced pantothenate kinase-associated neurodegeneration: A case report and literature review.

RATIONALE: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disease. Progressive motor symptoms such as dystonia and spasticity begin in childhood and relentlessly become incapacitating later in life. Treatments including anticholinergics and iron chelation are usually ineffective. Botulinum toxin type A (BoNT-A) is effective for adult patients with dystonia or spasticity. PATIENT CONCERNS: We reported a 10-year-old female patient with advanced PKAN, manifesting as generalized dystonia and spasticity. DIAGNOSIS: The patient was diagnosed with PKAN by a pediatric neurologist. INTERVENTIONS: The patient received BoNT-A injection. OUTCOMES: The effect was obvious at four weeks after the injection, with an improvement of 25% in Barry-Albright Dystonia Scale and 4% in Functional Independence Measure for Children score. Furthermore, there was a 3.8% reduction in Parenting Stress Index Short Form score and 8.3% improvement in Pain and Impact of Disability domain in the score of Cerebral Palsy Quality of Life for Children. LESSONS: BoNT-A injection was effective to improve functional independence and to alleviate stress of caregivers in the patient with advanced PKAN.

Deep brain stimulation in the globus pallidus compensates response inhibition deficits: evidence from pantothenate kinase-associated neurodegeneration.

Fronto-striatal loops are important for many cognitive control processes, like response inhibition, and it has been suggested that the globus pallidus is of particular importance for these processes. In the current study, we investigate the effect of deep brain stimulation in the GP on response inhibition processes by means of neurophysiological (EEG) methods. We perform a case-control study in neuroaxonal dystrophy pantothenate kinase-associated neurodegeneration (PKAN) using single-case statistics. We control the signal-to-noise ratio of the EEG data. The data show that disease-related changes in the globus pallidus lead to dysfunctions in response inhibition processes. Dysfunctions in the GP seem to affect controlled, but not automatized behavior as evidenced by an increased rate of false alarms and attenuation of inhibition-related neurophysiological correlates. With respect to controlled behavior in terms of response inhibition, it seems that pre-motor subprocesses and not evaluation subprocesses are affected. Deep brain stimulation in the globus pallidus seems to be able to compensate the effects of disease-related changes in this structure and normalizes response inhibition performance and their electrophysiological correlates in PKAN.

Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: novel mutations and neuropsychiatric phenotype in three adult patients.

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare neuropsychiatric syndromes characterized by iron accumulation in the basal ganglia. The pantothenate kinase-associated neurodegeneration (PKAN) was the first NBIA form to be genetically identified almost 15 years ago. Nowadays, eight types can be genetically distinguished. More recently, a novel NBIA was delineated and termed Static Encephalopathy of childhood with Neurodegeneration in Adulthood (SENDA), characterized by early intellectual disability followed by delayed progressive motor and cognitive deterioration with an onset in the second to third decade. Very recently, mutations in the WD repeat-containing protein 45 (WDR45) gene located on Xp11.23 were shown to be the causal factor. The protein encoded by WDR45 propels protein interaction important for autophagy. This form was therefore retermed Beta-propeller Protein Associated Neurodegeneration (BPAN). Here, the first three Dutch patients with genetically proven BPAN are comprehensively described with respect to course and neurological as well as neuropsychiatric phenotypes. All three showed a characteristic delayed progression of neurological symptoms with parkinsonism and prominent dystonia. Treatment with levodopa/carbidopa had limited effects only. Neuropsychiatric symptoms within the autistic and affective spectrum were present in the early phase of the disease. The specific course and prognosis should implicate restrained psychopharmacological interventions. The clinical picture and imaging hallmarks are often highly suggestive and should lead to suspect this specific disorder. However, the identification of a WDR45 mutation is needed for a definite diagnosis of BPAN.

Cognitive functioning in children with pantothenate-kinase-associated neurodegeneration undergoing deep brain stimulation.

AIM: To examine the cognitive functioning of young people with pantothenate-kinase-associated neurodegeneration (PKAN) after pallidal deep brain stimulation (DBS). PKAN is characterized by progressive generalized dystonia and has historically been associated with cognitive decline. With growing evidence that DBS can improve motor function in adults and children with PKAN, there is now the opportunity to study the cognitive profiles of these patients over time. METHOD: We present a case series of seven children (mean age 11 y 7 mo, SD 3 y 2 mo) undergoing bilateral pallidal DBS for the management of severe PKAN-associated dystonia. We administered standardized measures of intellectual ability and memory where possible, before DBS and 1 to 4 years after DBS. RESULTS: No cognitive decline was observed and scores improved in all but one child (whose dystonia could not be adequately controlled owing to multiple medical problems). In line with a stabilization or reduction in their dystonia, all but one child was able to tolerate longer assessment sessions and complete either the same or a greater number of subtests. INTERPRETATION: These findings suggest that apparent cognitive impairments may reflect difficulties in accessing cognition owing to severity of dystonia. Intellectual decline previously associated with PKAN may have been overestimated.

Intellectual and adaptive behaviour functioning in pantothenate kinase-associated neurodegeneration.

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN), an extremely rare autosomal recessive disorder resulting in iron accumulation in the brain, has a diverse phenotypic expression. Based on limited case studies of one or two patients, intellectual impairment is considered part of PKAN. Investigations of cognitive functioning have utilized specific neuropsychological tests, without attention to general intellectual skills or adaptive behaviour. METHODS: Sixteen individuals with PKAN completed measures of global intellectual functioning, and participants or care providers completed measures of adaptive behaviour skills and day-to-day functional limitations. Clinicians provided global ratings of condition severity. RESULTS: Testing with standardized measures documented varied phenotypic expression, with general cognitive skills and adaptive behaviour ranging from high average to well below average. Age of disease onset correlated with measures of intellectual functioning, adaptive functioning and disease severity. CONCLUSIONS: Findings support previously described clinical impressions of varied cognitive impairment and the association between age of onset and impairment. Further, they add important information regarding the natural history of the disease and suggest assessment strategies for use in treatment trials.

Psychotic disorder in a case with Hallervorden-Spatz disease.

OBJECTIVE: Hallervorden-Spatz disease is a rare autosomal recessive condition, with early onset of predominantly extrapyramidal dysfunction. The symptoms of the disease are dystonia, rigidity, choreoathetosis, pyramidal signs, and intellectual decline. Recent genetic studies mapped the disease to chromosome 20p12.3-p13, and identified mutations in the pantothenate kinase gene. This report describes a childhood onset case of Hallervorden-Spatz disease with schizophreniform psychotic symptoms. Former reports about the psychiatric comorbidity generally included depressive disorder. METHOD: A single case report. RESULTS: A 14-year-old boy with Hallervorden-Spatz disease presented a psychotic episode with prominent auditory hallucinations. Symptoms were relieved after neuroleptic treatment. CONCLUSION: To the authors' knowledge, this is the first published report of the disease with psychotic symptoms. The contribution of basal ganglia, with their wide projections, to the emergence of psychotic symptoms was discussed.

Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome.

BACKGROUND: Hallervorden-Spatz syndrome is an autosomal recessive disorder characterized by dystonia, parkinsonism, and iron accumulation in the brain. Many patients with this disease have mutations in the gene encoding pantothenate kinase 2 (PANK2); these patients are said to have pantothenate kinase-associated neurodegeneration. In this study, we compared the clinical and radiographic features of patients with Hallervorden-Spatz syndrome with and without mutations in PANK2. METHODS: One hundred twenty-three patients from 98 families with a diagnosis of Hallervorden-Spatz syndrome were classified on the basis of clinical assessment as having classic disease (characterized by early onset with rapid progression) or atypical disease (later onset with slow progression). Their genomic DNA was sequenced for PANK2 mutations. RESULTS: All patients with classic Hallervorden-Spatz syndrome and one third of those with atypical disease had PANK2 mutations. Whereas almost all mutations in patients with atypical disease led to amino acid changes, those in patients with classic disease more often resulted in predicted protein truncation. Patients with atypical disease who had PANK2 mutations were more likely to have prominent speech-related and psychiatric symptoms than patients with classic disease or mutation-negative patients with atypical disease. In all patients with pantothenate kinase-associated neurodegeneration, whether classic or atypical, T2-weighted magnetic resonance imaging (MRI) of the brain showed a specific pattern of hyperintensity within the hypointense medial globus pallidus. This pattern was not seen in any patients without mutations. CONCLUSIONS: PANK2 mutations are associated with all cases of classic Hallervorden-Spatz syndrome and one third of cases of atypical disease. A specific MRI pattern distinguishes patients with PANK2 mutations. Predicted levels of pantothenate kinase 2 protein correlate with the severity of disease.

Myopathic involvement in two cases of Hallervorden-Spatz disease.

Muscle biopsy was performed in two patients with Hallervorden-Spatz disease and increased serum creatine kinase levels. Morphological analysis showed myopathic signs such as subsarcolemmal accumulation of myeloid structures, dense bodies and debris, endomysial macrophage activation, focal necrosis and fiber splitting. We emphasize the finding of muscle involvement in Hallervorden-Spatz disease, like in other forms of neuroacanthocytosis.

Hallervorden-Spatz disease in a psychiatric setting.

Neurodegenerative disorders of sufficient severity to be lethal are also likely to generate psychiatric symptomatology. At times, behavioral changes may predate neurologic manifestations, whereas at other times disturbances in mental status and physical functioning may coexist. In either situation, accurate assessment and appropriate treatment may prove challenging. The case of Hallervorden-Spatz disease reported here illustrates this difficulty; the authors present it to highlight the general issues that often arise in this group of illnesses. In this patient, as well as in three of his relatives, initially subtle neurologic signs were preceded by and then intermingled with significant and sometimes severe symptoms of depression. The authors emphasize the importance of attending to the neurologic symptom picture and family history in order to more appropriately assess the psychiatric manifestations of the disorder. Knowledge of neurodegenerative illnesses, even those as admittedly rare as Hallervorden-Spatz disease, can facilitate accurate and prompt diagnostic assessment, guide treatment strategies (including avoidance of inappropriate interventions), and help to more realistically define outcome expectations.

Hallervorden-Spatz syndrome: clinical and magnetic resonance imaging correlations.

Two women with a presumptive diagnosis of Hallervorden-Spatz syndrome had a combination of dystonia and parkinsonism. One had retinitis pigmentosa. Neuropsychological testing revealed decreased verbal fluency and visuoconstructional and motor deficits. Magnetic resonance imaging performed with a high-field-strength unit (1.5 Tesla) showed striking abnormalities in the globus pallidus bilaterally ("eye-of-the-tiger" sign). Magnetic resonance imaging may prove useful in the diagnosis of Hallervorden-Spatz syndrome.