Alternative titles; symbols
SNOMEDCT: 2992000; ICD10CM: G23.0; ORPHA: 157850, 216866, 216873; DO: 3981;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20p13 | Neurodegeneration with brain iron accumulation 1 | 234200 | Autosomal recessive | 3 | PANK2 | 606157 |
A number sign (#) is used with this entry because neurodegeneration with brain iron accumulation-1 (NBIA1), originally known as Hallervorden-Spatz disease, is caused by homozygous or compound heterozygous mutation in the pantothenate kinase-2 gene (PANK2; 606157) on chromosome 20p13.
Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous disorder characterized 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., 2009).
NBIA1, or pantothenate kinase-associated neurodegeneration (PKAN), has been classified clinically as 'classic,' 'atypical,' or 'intermediate.' In the classic form, patients present within the first decade of life with rapidly progressing disease and loss of ambulation approximately 15 years later. 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 have 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. Most patients have the 'eye of the tiger' sign on brain MRI, although that finding is not pathognomonic for PANK2 mutations (Hayflick et al., 2003; Pellecchia et al., 2005; Kumar et al., 2006).
Genetic Heterogeneity of Neurodegeneration with Brain Iron Accumulation
Neurodegeneration with brain iron accumulation is an umbrella term that encompasses a group of genetically heterogeneous disorders. See also NBIA2A (256600) and NBIA2B (610217), both caused by mutation in the PLA2G6 gene (603604); NBIA3 (606159), caused by mutation in the FTL gene (134790); NBIA4 (614298), caused by mutation in the C19ORF12 gene (614297); NBIA5 (300894), caused by mutation in the WDR45 gene (300526); NBIA6 (615643), caused by mutation in the COASY gene (609855); NBIA7 (617916), caused by mutation in the REPS1 gene (614825); NBIA8 (617917), caused by mutation in the CRAT gene (600184); NBIA9 (620669), caused by mutation in the FTH1 gene (134770); and NBIA10 (604290), caused by mutation in the CP gene (117700).
There are additional disorders in which brain iron accumulation is observed; see, e.g., Kufor-Rakeb disease (606693), aceruloplasminemia (604290), and SPG35 (612319).
Gregory et al. (2009) and Schneider and Bhatia (2012) provided reviews of the different forms of neurodegeneration with brain iron accumulation.
The original description of this syndrome by Hallervorden and Spatz (1922) concerned a sibship of 12 in which 5 sisters showed clinically increasing dysarthria and progressive dementia, and at autopsy brown discoloration of the globus pallidus and substantia nigra. Familial cases have been reported by others as well. About 30 cases were reported by Meyer (1958). 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 and rigidity may involve muscles supplied by cranial nerves, resulting 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.
Elejalde et al. (1978) observed 5 affected persons in a kindred and suggested that the condition originated in central Europe. Elejalde et al. (1979) provided a clinical and genetic analysis. 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 11.18 years (SD = 7.8). The dopamine-neuromelanine system may be involved in the basic pathogenesis. Malmstrom-Groth and Kristensson (1982) 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 (1922) died before age 25. Jankovic et al. (1985) described a kindred ascertained through a 68-year-old man who died after 13 years of progressive dementia, rigidity, bradykinesia, mild tremor, stooped posture, slow and shuffling gait, dystonia, blepharospasm, apraxia of eyelid opening, anarthria, aphonia, and incontinence. 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, medulla, 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, died accidentally at age 46.
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, 1985; Tanfani et al., 1987; Sethi et al., 1988) suggested the possibility of an in vivo diagnosis. Angelini et al. (1992) presented the clinical and MRI findings of 11 patients diagnosed as having Hallervorden-Spatz disease. 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).
Higgins et al. (1992) reported an 11-year-old Mexican girl who developed spasticity of the lower limbs at 3 years of age after normal early development. She showed progressive decline, with loss of walking, language deterioration, generalized dystonia, and orofacial movements. She was mute by 8 years of age. At age 10, she showed impaired vision with pigmentary retinopathy and the 'eye of the tiger' sign on brain MRI. A peripheral blood smear and electron microscopy demonstrated marked acanthocytosis that was not due to an intrinsic erythrocyte protein defect. High-resolution lipoprotein electrophoresis demonstrated absence of the pre-beta fraction, with normal blood levels of cholesterol, triglycerides, high and low density lipoprotein cholesterol, and apolipoproteins A, B, and C. Higgins et al. (1992) noted the phenotypic overlap with NBIA1, but suggested the acronym 'HARP syndrome' (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) to describe the disorder. Walker et al. (2021) noted that the term 'hypoprebetalipoproteinemia' is outdated and provides no useful clinical meaning. Walker et al. (2021) suggested that what has been called 'HARP syndrome' is actually a form of NBIA1 and that the HARP acronym should no longer be used.
Casteels et al. (1994) described an 8-year-old girl who presented with 3 years of visual impairment and bilateral optic atrophy before developing dystonia and other typical features of Hallervorden-Spatz disease. The MRI demonstrated extremely low signal intensity of the globus pallidus 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 otherwise typical Hallervorden-Spatz disease.
Although there is no clinical myopathy associated with Hallervorden-Spatz disease, Malandrini et al. (1995) found similar morphologic changes in skeletal muscle in 2 unrelated patients with typical Hallervorden-Spatz disease. 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.
Orrell et al. (1995) reported an 18-year-old woman who presented with longstanding intellectual subnormality, night blindness, and a 2-year history of orobuccolingual dystonia causing dysarthria and dysphagia. Investigation showed 53% acanthocytosis and hypoprebetalipoproteinemia, and ERG was typical of tapetoretinal degeneration. MRI showed the 'eye of the tiger' sign. The patient's sister and mother had a similar lipid disorder and acanthocytosis, but no neurologic or retinal disease.
Pellecchia et al. (2005) reported 16 patients with PKAN confirmed by genetic analysis. Clinically, 5 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 and obsessive-compulsive features similar to Tourette syndrome (137580). The most common features were corticospinal signs, dysarthria, dystonia, and rigidity. Three patients had pigmentary retinopathy, and almost 50% of patients had psychiatric involvement, including hyperactivity and depression. All patients had the characteristic 'eye of the tiger' sign on brain MRI.
Delgado et al. (2012) reported 20 patients from the Dominican Republic with PKAN associated with a homozygous Y227C mutation in the PANK2 gene. There was also a 7-year-old girl without symptoms who was homozygous for the Y227C mutation ('preclinical' case). All patients originated from the area around the town of Cabral in the southwest region of the Dominican Republic. The patients, who ranged in age from 7 to 41 years, had symptom onset between 8 and 14 years. The disorder was characterized by truncal dystonia followed by retrocollis, oromandibular and facial dystonia, chorea, and dysarthria. Intellectual decline was only minor or even absent, and there was no pigmentary retinopathy. Brain imaging showed iron deposition in the globus pallidus. The 'eye of the tiger' sign was found in 15 patients, but was absent in 6. Schiessl-Weyer et al. (2015) examined erythrocyte morphology in 25 patients from the Dominican Republic with PKAN, most of whom were previously reported by Delgado et al. (2012). Acanthocyte levels above 10% were found in 45% of patients, and 2 patients had acanthocyte levels above 20%; no red cell abnormalities were found in 34% of patients. Mild acanthocytosis was observed in 39% of heterozygous carriers, and elevated acanthocytes were found in 6% of heterozygous carriers. Most (80%) controls had no acanthocytosis, although 2 had mild and 2 had elevated acanthocytes. Schiessl-Weyer et al. (2015) noted that PANK2 and other enzymes of the coenzyme A biosynthetic pathway are normal constituents of the erythrocyte cytosol; they hypothesized that reduced CoA levels could result in aberrant lipid-based signaling processes and dysfunctional organization of protein complexes at the erythrocyte plasma membrane. The findings indicated that the PANK2 Y227C mutation alone is not sufficient to determine acanthocytic shape transformation in erythrocytes and that additional factor(s) or condition(s) are necessary for acanthocytosis to occur.
Differential Diagnosis
Using single photon emission computed tomography (SPECT), Cossu et al. (2005) found normal striatal presynaptic dopamine activity in 2 sibs with PKAN confirmed by genetic analysis. The authors suggested that these SPECT findings, in combination with the classic MRI findings in PKAN, would aid in the differential diagnosis of the disorder.
The transmission pattern of NBIA1 in the families reported by Zhou et al. (2001) was consistent with autosomal recessive inheritance.
The transmission pattern of NBIA1 in the families reported by Ching et al. (2002) and Houlden et al. (2003) was consistent with autosomal recessive inheritance.
Using homozygosity mapping in a large Amish family, Taylor et al. (1996, 1996) mapped Hallervorden-Spatz disease to 20p13-p12.3. 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 13.75 at theta = 0.0 for 1 polymorphic microsatellite marker. 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 D20S906 and D20S116. Taylor et al. (1996) found locus heterogeneity for the disorder; one Japanese family did not show linkage to this region, indicating the existence of another locus for the disorder.
Using linkage analysis of an extended Amish pedigree, Zhou et al. (2001) narrowed the critical interval on chromosome 20p13 to a 1.4-Mb interval that contained 21 known or predicted genes.
In affected members of an Amish family with Hallervorden-Spatz syndrome, Zhou et al. (2001) identified a homozygous 7-bp deletion (606157.0001) in the coding sequence of the PANK2 gene. 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. DNA from individuals with atypical PKAN also demonstrated missense mutations in PANK2. 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 even into their thirties carried a homozygous missense mutation (606157.0007). In the group studied, most mutations were unique, with a notable exception of the gly411-to-arg mutation (606157.0002), which was present in both classic and atypical individuals.
In 16 patients with PKAN, Pellecchia et al. (2005) identified 12 mutations in the PANK2 gene, including 5 novel mutations.
Ching et al. (2002) studied the original patient reported by Higgins et al. (1992) and identified a homozygous nonsense mutation in the PANK2 gene (R371X; 606157.0011).
In a patient initially reported by Orrell et al. (1995), Houlden et al. (2003) identified compound heterozygosity for mutations in the PANK2 gene: a missense mutation (M327T; 606157.0012) and a splice site mutation (606157.0013). The patient's mother and sister, both of whom had acanthocytosis and hypoprebetalipoproteinemia without neurologic abnormalities, were heterozygous for the splice site mutation, whereas her unaffected father was heterozygous for the missense mutation.
Hayflick et al. (2003) studied 123 patients from 98 families with a diagnosis of Hallervorden-Spatz syndrome and classified them as having classic disease or atypical disease. 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.
Pellecchia et al. (2005) found no genotype/phenotype correlations among 16 patients with PKAN confirmed by genetic analysis.
Hartig et al. (2006) identified homozygous or compound heterozygous PANK2 mutations in 48 of 72 patients with PKAN. Deletions accounted for 4% of mutated alleles. There was a correlation between predicted loss-of-function alleles and earlier age at disease onset.
Drecourt et al. (2018) found that cells derived from NBIA patients with PANK2 mutations showed a significant increase (10- to 30-fold change) in cellular iron content when incubated with iron compared to controls. In response to high iron, patient cells showed a normal and appropriate decrease in transferrin receptor (TFRC; 190010) mRNA levels, but the amount of TFRC did not decrease in patient cells, suggesting impaired posttranslational lysosomal-based degradation of TFRC. Patient cells showed impaired transferrin (190000) and TFRC trafficking and recycling compared to controls, with clustering at the surface and in the perinuclear region, as well as abnormally enlarged lysosomes. Patient cells also showed decreased palmitoylation of TFRC, which is necessary for regulating TFRC endocytosis. Addition of the antimalarial agent artesunate rescued abnormal TFRC palmitoylation and decreased iron content in cultured patient fibroblasts. Similar findings were observed in studies of cells from NBIA patients due to mutations in other NBIA-associated genes (PLA2G6, FA2H (611026), C19ORF12, REPS1, and CRAT). Drecourt et al. (2018) concluded that NBIA results from defective endosomal recycling and should be regarded as a disorder of cellular trafficking, whatever the original genetic defect.
In affected members from 4 Dutch families with pantothenate kinase-associated neurodegeneration, Rump et al. (2005) identified a 3-bp deletion in the PANK2 gene (606157.0014). Haplotype analysis suggested a founder effect that arose in Friesland, a northern province of the Netherlands, at the beginning of the ninth century, approximately 38 generations ago. Rump et al. (2005) provided a brief history of the geographic isolation of the region.
Based on a literature review of PANK2 mutations in patients with NBIA1 and a bioinformatic analysis of PANK2 variants in the gnomAD database, Brezavar and Bonnen (2019) estimated an incidence of 2 in 1 million live births globally outside of Africa and an incidence of 1 in 1.5 million live births in the African population.
Kuo et al. (2005) generated a mouse knockout of the murine Pank2 gene. 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. In 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 Hallervorden (1882-1965), whose name, with that of Hugo Spatz, is linked to this disorder, made important contributions to neurologic science (Richardson, 1990). However, as detailed by Shevell (1992), his active involvement in a euthanasia program in Germany during World War II raises serious questions about the moral obligations of medical science. Muller-Hill (1987) reviewed much of this information in his 'Murderous Science.' No euthanasia law was ever enacted in the Third Reich. Rather, physicians were empowered to carry out 'mercy 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 (123400) 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 (1992). In responding to the article by Shevell (1992), several authors (e.g., Gordon, 1993) suggested that Hallervorden's name should be removed from this disorder. Shevell (1992) 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, 1922). Zhou et al. (2001) suggested that this disorder be referred to as 'pantothenate kinase-associated neurodegeneration' to avoid the objectionable eponym and to reflect the etiology of the disorder.
Shevell (2003) reviewed the unhappy history of Adolf Hitler's 'Aktion T-4' program, which resulted in the deaths of 70,273 individuals 'judged to be incurably ill' and provided Hallervorden with his study material.
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