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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Hallervorden-Spatz disease HSD is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. Hallervorden and Spatz first described the disease, in as a form of synxrome brain degeneration characterized by iron deposition in the brain. Here we present four HSD cases with different clinical pictures. The term neurodegeneration with brain iron accumulation type 1, instead of HSD, eventually came to be used for this condition;[ 1 ] although, the most recent term for the disorder is pantothenate kinase PANK2 – shndrome neurodegeneration.
Onset most commonly occurs in late childhood or early adolescence. The classic presentation is in the late part of the first hallervorden-spattz or the early part of the second decade, when the individual is between ages 7 years and 15 years. However, the disease has been reported in infancy, and cases with adult onset have been described as well. HSD is relentlessly progressive.
The course is characterized by progressive dementia, corticospinal signs e. The course of the disease usually proceeds over years and affected individuals typically die in the hallerborden-spatz or third decade, but case reports describe patients surviving 30 years. The disease can be familial or sporadic. When familial, HSD is inherited recessively; it has been linked to chromosome A year-old girl was relatively asymptomatic until the age of 15 years when she started developing dysphagia, dysarthria, and dysphonia.
These abnormalities progressed over 4 years with anarthria, severe dysphagia and abnormal movement of tongue [ Video 1 ].
There is no impairment of higher cortical functions. No visual abnormalities were detected. No significant family history was obtained. Neurological examination revealed sever slurred speech; sever tongue dystonia, mild bilateral rigidity on lower limbs, hyperreflexia, and auto babinski. Laboratory investigations including serum copper hallsrvorden-spatz ceruloplasmin levels were normal. Magnetic resonance imaging MRI scan revealed small hyper intensity in the inner part of both GP, surrounded by the hypo-intense rim peripherally on T2 [ Figure 1 ].
A year-old girl was relatively asymptomatic until age of 14 years when she started walking on toes and unsteady gait. Gradually, she developed motor sydrome in hands, dysphagia, and dysarthria. She has positive family history for nearly similar symptoms in her cousin. Neurological examination revealed hyper-extension in neck muscles and because of that she was unable to look downward.
She had slurred speech and difficulty in chewing. Dystonia was present on both upper and lower limbs. Axial rigidity was prominent finding. She had generalized rigidity. Deep tendon reflexes were exaggerated and babinski sign was positive [ Video 2 ]. Lab data were negative for Wilson serology. MRI scans revealed small hyper intensity in the inner part of both GP, surrounded by the hypo-intense rim peripherally on T2 [ Figure 2 ]. Magnetic resonance imaging hzllervorden-spatz small hyper intensity in inner part of both GP, surrounded by hypointense rim peripherally on T2.
A year-old woman who presented with limb tremor and mild slurring in speech. She was asymptomatic until age 17 when she developed dysarthria and right hand tremor.
Gradually, the symptom worsened and it propagated to left foot and then left hand and right foot involved too [ Video 3 ]. Neurological examination revealed mild dysarthria, no rigidity or spasticity was detected. She had severe asymptomatic twisting tremor in hands.
In lower limbs, tremor was more severe on the left side. Serology for Wilson disease was negative. MRI scan revealed small hyper intensity in inner part of both GP, surrounded by the hypo-intense rim peripherally on T2 [ Figure 3 ].
After 5 years of disease start she had a successful pregnancy, but after that her symptoms worsened. A year-old man presented with dysphagia, motor difficulties, and speech problems.
His symptoms started 6 years ago with mild dysphagia and unsteady gait and abnormal posture of the right hand. In a short time, his dystonia propagated to other limbs and dysphagia worsened and he developed incomprehensive speech. When After start walking, a sudden severe pain pop out in both lower limbs and by standing and short resting it get resolved fast.
Neurological examination revealed marked diffuse rigidity both pyramidal and extra pyramidal. Deep tendon reflexes were brisk. Babinski sign was positive. After seating for a short time, he was unable to maintain upright posture and bending posture is produced.
Because of severe dystonia in limbs and tongue muscles, he was unable to eat easily as you can see in movie. Serum copper and ceruloplasmin levels were normal. MRI scan revealed small hyper-intensity in inner part of both GP, surrounded by the hypo-intense rim peripherally on T2 [ Figure 4 ].
The exact etiology of HSD is not known. One suggestion states that abnormal peroxidation of lipofuscin to neuromelanin and deficient cysteine dioxygenase lead to abnormal iron accumulation in the brain. While portions of the globus pallidus and pars reticulata of the substantia nigra SN have high iron content in healthy individuals, individuals with HSD have excess amounts of iron deposited in these areas.
However, the exact role of iron in the etiology of this disease remains unknown.
However, whether the deposition of iron in basal ganglia in HSD is the cause or consequence of neuronal loss and gliosis is not clear. Decreased activity of the enzyme cysteine di-oxygenase was demonstrated in 1 affected child. However, these findings were not confirmed in adult patients. Deficiency of PANK2 may lead to accumulation of cysteine and cysteine-containing compounds in the basal ganglia. This causes chelation of iron in the globus pallidus and free radical generation as a result of rapid auto-oxidation of cysteine in the presence of iron.
Such mutations result in an autosomal recessive inborn error of coenzyme A metabolism called PANK2— associated neurodegeneration. Pathologic evaluation reveals characteristic rust-brown discoloration of the globus pallidus and SN pars reticulata secondary to iron deposition.
Clinical manifestations of HSD vary from patient to patient. The symptoms usually begin in the first decade with a motor disorder of extrapyramidal type and gait difficulty. Symptoms dominating the clinical picture include rigidity of extremities, slowness of movement, dystonia, choreoathetosis, and tremor. In some patients, extrapyramidal dysfunction may be delayed for several years as spasticity and dysarthria may be the presenting symptoms.
Physical examination reveals signs consistent with extrapyramidal and corticospinal dysfunction. In addition to rigidity, dystonia, and chorea, patients may experience spasticity, brisk reflexes, and extensor plantar responses. Based on the common clinical features, the following diagnostic criteria for HSD have been proposed.
None of the exclusionary factors should be present. The differential diagnosis of HSD includes other diseases presenting with extrapyramidal-pyramidal-dementia complex. No biochemical markers have been found in HSD. Levels of copper, ceruloplasmin, lipids, amino acids, and acanthocytes typically are measured in the blood to exclude other conditions.
Radionuclide scan reveals increased uptake of iron by the basal ganglia. Cultured skin fibroblasts have been reported to accumulate iron 59 Fe transferrin, but the isotope is no longer available for human use. Increased platelet monoamine oxidase — B activity has been reported.
CT imaging is not very helpful in the diagnosis of HSD but may exhibit hypo-density in the basal ganglia and some atrophy of the brain. Calcification in the basal ganglia in the absence of any atrophy also has been described. These imaging features are fairly diagnostic of HSD and have been termed the eye-of-the-tiger sign. A study by McNeill et al. The hyper-intensity represents pathologic changes, including gliosis, demyelination, neuronal loss, and axonal swelling, and the surrounding hypointensity is due to the loss of signal secondary to iron deposition.
The treatment of patients with HSD remains directed toward symptomatic findings. Tremor in patients with HSD responds best to dopaminergic agents. The anticholinergic agent benztropine helps rigidity and tremor. Benzodiazepines have been tried for choreoathetotic movements. Hypertonia is usually a combination of rigidity and spasticity and may be difficult to treat. Dopamine agonists and anticholinergics may help to reduce rigidity. Baclofen in moderate doses relieves the stiffness and spasms and can reduce dystonia.
Symptoms such as drooling and dysarthria can be troublesome. Treat excessive drooling with a medication such as methscopolamine bromide. Dysarthria may respond to medications used for rigidity and spasticity. Speech therapy also may be useful, and computer-assisted devices may be employed in the treatment of patients with advanced cases. Gastrostomy feeding may be necessary in advanced cases of dysphagia. A multidisciplinary team approach involving physical, occupational and speech therapists may be needed in selected patients with a protracted course to improve functional skills and communication.
Systemic chelating agents, such as desferrioxamine have been used in an attempt to remove excess iron from the brain, but these have not proved beneficial. Dementia is progressive, and no treatment has proved clearly effective. As previously mentioned dopaminergic agents, such as levodopa and bromocriptine can produce modest improvements in dystonia. If dopaminergic agents are not effective against dystonia, anticholinergics can be used, but they offer only transient relief.