Hallervorden-Spatz disease now more commonly known as Pantothenate kinase -associated neurodegeneration (PKAN) is a rare autosomal. Pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation 1 (NBIA1), also called Hallervorden–Spatz syndrome, is a degenerative disease of the. Hallervorden-Spatz syndrome was first described in by Drs. Julius Hallervorden and Hugo Spatz with their study of a family of 12 in which five sisters.
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CC HPO: C ] – Classic: C ] – Atypical: C ] – Intermediate: HARP syndrome is a rare allelic disorder with syndro,e less severe phenotype and the presence of hypobetalipoproteinemia and acanthocytosis. Neurodegeneration with brain iron accumulation is a genetically heterogeneous disorder halledvorden-spatz by progressive iron accumulation in the basal ganglia and other regions of the brain, resulting in extrapyramidal movements, such as parkinsonism and dystonia.
Age at onset, severity, and cognitive involvement are variable review by Gregory et al. Panthothenate kinase-associated neurodegeneration has been classified clinically as ‘classic,’ ‘atypical,’ or ‘intermediate. In the atypical form, patients have onset in the second decade with slow progression and maintain independent ambulation after 15 years.
In the intermediate form, patients hallerorden-spatz early onset and slow progression or later onset and rapid progression. Patients with early onset tend to develop pigmentary retinopathy, whereas those with later onset tend to have speech disorders and psychiatric features.
All patients have the ‘eye of the tiger’ sign on brain MRI Hayflick et al. They reported 2 unrelated adult patients with cognitive dysfunction who had the characteristic sign on MRI but sydrome not have mutations in the PANK2 gene. In addition, some patients with Kufor-Rakeb syndromealso known as Parkinson disease-9 PARK9have iron deposition in the basal ganglia.
Neurodegeneration with brain iron accumulation is an umbrella term that encompasses a group of genetically heterogeneous disorders. See review of Schneider and Bhatia on syndromes of neurodegeneration with brain iron accumulation, including Kufor-Rakeb disease and aceruloplasminemia The original description of this syndrome by Hallervorden and Spatz concerned a sibship of 12 in which 5 sisters showed clinically increasing dysarthria and progressive dementia, and at autopsy brown discoloration of the globus syndroje and substantia nigra.
Familial cases have been reported by others as well. Hallervorden-spaatz 30 cases were reported by Meyer Clinically the condition is characterized by progressive rigidity, first in the lower and later in the upper extremities.
An equinovarus deformity of the foot has been the first sign in several cases. Involuntary movements of choreic or athetoid type sometimes precede or accompany rigidity. Both involuntary movements jallervorden-spatz rigidity may involve muscles supplied by cranial nerves, syndroms in difficulties in articulation and swallowing.
Mental deterioration and epilepsy occur in some. Onset is in the first or second decade and death usually occurs before the age of 30 years.
This disorder affects the muscular tone and voluntary movements progressively, making coordinated movements and chewing and swallowing almost impossible.
Mental deterioration, emaciation, severe feeding difficulties, and visual impairment occur commonly as late manifestations. The mean survival time after diagnosis was The dopamine-neuromelanine system may be involved in the basic pathogenesis. Malmstrom-Groth and Kristensson reported the cases of 2 second cousins who developed clinical signs of a progressive extrapyramidal motor disorder and mental retardation and died at ages 8 and 11 years.
Iron deposits and axonal dystrophy were found in the pallidum. All 5 sibs in the family originally studied by Hallervorden and Spatz died before age At autopsy, he had generalized brain atrophy with large deposits of iron pigment in the globus pallidus, caudate and substantia nigra.
Axonal spheroids were found in the globus pallidus, substantia nigra, hallerorden-spatz, and spinal cord. Neurochemical analysis of the brain showed marked loss of dopamine in the nigral-striated areas with relative preservation of dopamine in the limbic areas. Of his 4 sibs, 3 were also affected. The youngest, a sister, had been diagnosed as having Alzheimer disease. The parents, nonconsanguineous, hallervoren-spatz accidentally at age The diagnosis of Hallervorden-Spatz disease has usually been made postmortem; however, the description of magnetic resonance imaging MRI alterations in the basal ganglia Littrup and Gebarski, ; Tanfani et al.
OMIM Entry – # – NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1; NBIA1
Generalized dystonia with predominance of oromandibular involvement, behavioral changes followed by dementia, and retinal degeneration were present in all the patients. MRI pallidal abnormalities consisted of decreased signal intensity in T2-weighted images, compatible with iron deposits, and of a small area of hyperintensity in its internal segment ‘eye of the tiger’ sign.
The MRI demonstrated extremely low signal intensity of the globus pallitus and in the zona reticularis of the substantia nigra on the T2-weighted images. The red nuclei were spared. The authors suggested that a larger series of patients with Hallervorden-Spatz disease should be studied ophthalmologically to exclude the coincidental occurrence of optic atrophy in a patient with halllervorden-spatz typical Hallervorden-Spatz disease.
Although there is no clinical myopathy associated with Hallervorden-Spatz disease, Malandrini et al. Both of these patients had mild elevation of serum creatine kinase. Histologic analysis of biopsy quadriceps muscle demonstrated subsarcolemmal accumulation of myeloid structures, dense bodies and debris, endomysial macrophage activation, focal necrosis, and fiber splitting. Clinically, ssyndrome patients had classic disease, 4 patients had atypical disease, and 4 had intermediate disease; 3 patients could not be classified.
Regardless of clinical type, most patients presented with gait abnormalities or writing difficulty. Two patients presented with psychomotor delay, and 2 presented with motor tics syndromme obsessive-compulsive features similar to Tourette syndrome The most common features were corticospinal signs, dysarthria, dystonia, and rigidity.
All patients had the characteristic ‘eye of the tiger’ sign on brain MRI. Using homozygosity mapping in a large Amish family, Taylor et hallervordsn-spatz. Analysis of 9 other families from New Zealand, Australia, Spain, and Italy supported linkage to this region with a total maximum 2-point lod score of Homozygosity in the Amish family and recombinant haplotypes in 3 of the other families suggested that the gene involved is located in a 4-cM interval between D20S and D20S Using linkage analysis of an extended Amish pedigree, Zhou et al.
In affected members of an Amish family with Hallervorden-Spatz syndrome, Zhou et al. Additional missense and null mutations in the PANK2 gene were identified in 32 of 38 individuals with classic Hallervorden-Spatz syndrome.
Mutations on both alleles could be accounted for in 22 of these 32 individuals.
These individuals have later onset, and their diverse phenotypes include early-onset Parkinson disease, severe intermittent dystonia, stuttering with palilalia or facial tics with repetitive hair caressing; all had evidence of increased basal ganglia iron. One consanguineous family with pigmentary retinopathy and late-onset dystonia but without radiographic evidence of brain iron accumulation syndfome into their thirties carried a homozygous missense mutation In the group studied, most mutations were unique, with a notable exception of the glyto-arg mutation 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 classic or atypical PKAN, T2-weighted 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 PANK2 mutations. Predicted levels of pantothenate kinase-2 protein correlated with the severity of the disease.
There was a correlation between predicted loss-of-function alleles and earlier age at disease onset. Patient cells showed impaired transferrin and TFRC trafficking and recycling compared to controls, with clustering at the surface and in the perinuclear region, as well as abnormally enlarged lysosomes.
Addition of the antimalarial agent artesunate rescued abnormal TFRC palmitoylation and decreased iron content in cultured patient fibroblasts. In affected members from 4 Dutch families with pantothenate sydnrome neurodegeneration, Rump et al.
Haplotype analysis suggested a founder effect that arose in Hallervorden-saptz, a northern province of the Netherlands, at the beginning of the ninth century, approximately 38 generations ago. Homozygous null mice gradually developed retinal degeneration with progressive photoreceptor decline, significantly lower scotopic a- and b-wave amplitudes, decreased cell number and disruption of the outer segment, and reduced pupillary constriction response.
Homozygous male mutants were infertile due to azoospermia, a condition that was not appreciated in affected humans. Hal,ervorden-spatz contrast to the human, homozygous null mice exhibited no basal ganglia changes or dystonia. By immunohistochemistry, Pank2 was localized to mitochondria in both retina and spermatozoa.
Julius Hallervordenwhose name, with that of Hugo Spatz, is linked to this disorder, made important contributions to neurologic science Richardson, However, as detailed by Shevellhis active involvement in a euthanasia program in Germany during World War II raises serious questions about the moral obligations of medical science.
Muller-Hill reviewed much of this information in his ‘Murderous Science. Rather, physicians were empowered to carry out hallervogden-spatz killings’ but were never obliged to do so. There was never a direct order to participate, and refusal to cooperate did not result in legal action or professional setback.
Active opponents were many and included such prominent physicians as Creutzfeldt, another neuropathologist for whom Creutzfeldt-Jakob disease is named. Hallervorden’s enthusiastic encouragement of the killings and the other aspects that led to dehumanization of both the victims and the participants was detailed by Shevell In responding to the article by Shevellseveral authors e. Shevell suggested that the disease might be called ‘Martha-Alma disease’ for the 2 unfortunate sisters whose brains were first dissected in the original description of the condition Hallervorden and Spatz, Shevell reviewed the unhappy history of Adolf Hitler’s ‘Aktion T-4’ program, which resulted in the deaths of 70, individuals ‘judged to be incurably ill’ and provided Hallervorden with his study material.
Optic atrophy as the presenting sign in Hallervorden-Spatz syndrome. Impaired transferrin receptor palmitoylation and recycling in neurodegeneration with brain iron accumulation. Genetic and nosologic considerations in Hallervorden-Spatz disease. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. Eigenartige Erkrankung im extrapyramidalen System mit besonderer Beteiligung des Globus pallidus und der Substantia nigra.: Ein Beitrag zu den Beziehungen zwischen diesen beiden Zentren.
Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome.
Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism.
Pantothenate Kinase-Associated Neurodegeneration – NORD (National Organization for Rare Disorders)
The ‘eye-of-the-tiger’ sign is not pathognomonic of the PANK2 mutation. Hallervorden-sparz of pantothenate kinase 2 Pank2 in mice leads to retinal degeneration and azoospermia. MR imaging of Hallervorden-Spatz disease.