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Susan J Hayflick

Publications and source records attributed to Susan J Hayflick.

At least 19 recordsLinked to original sources
PubMed2006

PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.

Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.

Brain↗
PubMed2006

Neurodegeneration with brain iron accumulation: from genes to pathogenesis.

Neurodegeneration with brain iron accumulation comprises a clinically and genetically heterogeneous collection of disorders that share key features. These include progressive neurological disease accompanied by high basal ganglia iron and axonal dystrophy. To date, 2 genetic forms have been associated with mutations in PANK2 and PLA2G6, both of which encode proteins that are critical to membrane integrity. The intersection of pathways perturbed by defects in these 2 genes now enables us to test hypotheses of a common pathogenesis and ask why iron accumulates. The mechanisms implicated may contribute to our understanding of more common neurodegenerative disorders with iron dyshomeostasis, including Parkinson and Alzheimer disease.

Brain↗
PubMed2005

Novel compound heterozygous mutations in the PANK2 gene in a Chinese patient with atypical pantothenate kinase-associated neurodegeneration.

We investigated the presence of mutations in the pantothenate kinase (PANK2) gene in a 27-year-old male Chinese patient with atypical pantothenate kinase-associated neurodegeneration (PKAN), formerly Hallervorden-Spatz syndrome. Automated DNA sequence analyses revealed compound heterozygous mutations in the exon 3 and 5. This patient had a 10-year history of PKAN characterized by a slight tremor of the right hand when writing at onset and a slow progressive rigidity of the neck and the right arm and resting tremor in upper extremities. Dysarthria, dysphagia, and dystonic-athetoid movements of the face and right fingers were marked. Magnetic resonance showed the typical "eye-of-the-tiger" sign.

Adult↗
PubMed2005

Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome).

PURPOSE: The onset of pantothenate kinase-associated neurodegeneration (PKAN) occurs in the first and second decade of life and a pigmentary retinal degeneration is a feature of the disorder. Since the neuro-ophthalmologic and electroretinographic (ERG) features have never been well delineated, we describe them in 16 patients with PKAN. DESIGN: Observational case series. METHODS: Sixteen patients with genetic and neuroimaging-confirmed PKAN were examined. Ten underwent neuro-ophthalmologic examination and all had ERGs. RESULTS: Of the 10 who underwent neuro-ophthalmologic examination, all showed saccadic pursuits and eight showed hypometric or slowed vertical saccades. Seven of eight had inability to suppress the vestibulo-ocular reflex; two patients could not cooperate. Two had square wave jerks and four had poor convergence. Vertical optokinetic responses were abnormal in five, and two patients had blepharospasm. Eight patients had sectoral iris paralysis and partial loss of the pupillary ruff consistent with Adie's pupils in both eyes. Only four of 10 examined patients showed a pigmentary retinopathy, but 11 of 16 had abnormal ERGs ranging from mild cone abnormalities to severe rod-cone dysfunction. No patient had optic atrophy. The PANK2 mutations of all of the patients were heterogeneous. CONCLUSIONS: Adie's-like pupils, abnormal vertical saccades, and saccadic pursuits were very common. These findings suggest that mid-brain degeneration occurs in PKAN more frequently than previously thought. ERG abnormalities were present in approximately 70% and no patient had optic atrophy. Although genotype-ocular phenotype correlations could not be established, allelic differences probably contributed to the variable clinical expression of retinopathy and other clinical characteristics in these patients.

Adolescent↗
PubMed2005

Neurodegeneration with brain iron accumulation.

Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive extrapyramidal disorders with radiographic evidence of focal iron accumulation in the brain, usually in the basal ganglia. Patients previously diagnosed with Hallervorden-Spatz syndrome fall into this category. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia and pigmentary retinopathy in children or speech and neuropsychiatric disorders in adults. In addition, a specific pattern on brain MRI, called the eye-of-the-tiger sign, is virtually pathognomonic for the disease. Pantothenate kinase is essential to coenzyme A biosynthesis, and the PANK2 protein is targeted to the mitochondria. Hypotheses of PKAN pathogenesis are based on the predictions of tissue-specific coenzyme A deficiency and the accumulation of cysteine-containing substrates. Identification of the major NBIA gene has led to more accurate clinical delineation of the diseases that comprise this group, a molecular diagnostic test for PKAN, and hypotheses for treatment.

Animals↗
PubMed2004

Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia.

Pantothenate kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz syndrome) is a rare but devastating neurodegenerative disorder, resulting from an inherited defect in coenzyme A biosynthesis. As pathology in the human condition is limited to the central nervous system, specifically the retina and globus pallidus, we have generated a mouse knock-out of the orthologous murine gene (Pank2) to enhance our understanding of the mechanisms of disease and to serve as a testing ground for therapies. Over time, the homozygous null mice manifest retinal degeneration, as evidenced by electroretinography, light microscopy and pupillometry response. Specifically, Pank2 mice show progressive photoreceptor decline, with significantly lower scotopic a- and b-wave amplitudes, decreased cell number and disruption of the outer segment and reduced pupillary constriction response when compared with those of wild-type littermates. Additionally, the homozygous male mutants are infertile due to azoospermia, a condition that was not appreciated in the human. Arrest occurs in spermiogenesis, with complete absence of elongated and mature spermatids. In contrast to the human, however, no changes were observed in the basal ganglia by MRI or by histological exam, nor were there signs of dystonia, even after following the mice for one year. Pank2 mice are 20% decreased in weight when compared with their wild-type littermates; however, dysphagia was not apparent. Immunohistochemistry shows staining consistent with localization of Pank2 to the mitochondria in both the retina and the spermatozoa.

Animals↗
PubMed2004

Postmortem molecular screening in unexplained sudden death.

OBJECTIVES: We examined the prevalence of defects in arrhythmia-related candidate genes among patients with unexplained sudden cardiac death (SCD). BACKGROUND: Patients with unexplained sudden death may constitute up to 5% of overall SCD cases. For such patients, systematic postmortem genetic analysis of archived tissue, using a candidate gene approach, may identify etiologies of SCD. METHODS: We performed analysis of KCNQ1 (KVLQT1), KCNH2 (HERG), SCN5A, KCNE1, and KCNE2 defects in a subgroup of 12 adult subjects with unexplained sudden death, derived from a 13-year, 270-patient autopsy series of SCD. Archived, paraffin-embedded myocardial tissue blocks obtained at the original postmortem examination were the source of deoxyribonucleic acid for genetic analysis. RESULTS: Two patients were found to have the same HERG defect, a missense mutation in exon 7 (nucleotide change G1681A, coding effect A561T). The mutation was heterozygous in Patient 1, but Patient 2 appeared to be homozygous for the defect. Patch-clamp recordings showed that the A561T mutant channel expressed in human embryonic kidney cells failed to generate HERG current. Western blot analysis implicated a trafficking defect in the protein, resulting in loss of post-translational processing from the immature to the mature form of HERG. No mutations were detected among the remaining four candidate genes. CONCLUSIONS: In this autopsy series, only 2 of 12 patients with unexplained sudden death were observed to have a defect in HERG among five candidate genes tested. It is likely that elucidation of SCD mechanisms in such patients will await the discovery of multiple, novel arrhythmia-causing gene defects.

Adult↗
PubMed2004

Clinical heterogeneity of neurodegeneration with brain iron accumulation (Hallervorden-Spatz syndrome) and pantothenate kinase-associated neurodegeneration.

Hallervorden Spatz syndrome (HSS), also referred to as neurodegeneration with brain iron accumulation (NBIA), is a rare inherited neurodegenerative disorder with childhood, adolescent, or adult onset. Patients with HSS/NBIA have a combination of motor symptoms in the form of dystonia, parkinsonism, choreoathetosis, corticospinal tract involvement, optic atrophy, pigmentary retinopathy, and cognitive impairment. After the recent identification of mutations in the PANK2 gene on chromosome 20p12.3-p13 in some patients with the HSS/NBIA phenotype, the term pantothenate kinase-associated neurodegeneration (PKAN) has been proposed for this group of disorders. To characterize clinically and genetically HSS/NBIA, we reviewed 34 affected individuals from 10 different families, who satisfied the inclusion criteria for NBIA. Relatives of patients who had clinical, magnetic resonance imaging (MRI), or pathological findings of NBIA were included in the study. Four patients were found to have mutations in the pantothenate kinase 2 (PANK2) gene. We compared the clinical features and MRI findings of those with and without PANK2 mutations. The presence of mutation in the PANK2 gene is associated with younger age at onset and a higher frequency of dystonia, dysarthria, intellectual impairment, and gait disturbance. Parkinsonism is seen predominantly in adult-onset patients whereas dystonia seems more frequent in the earlier-onset cases. The phenotypic heterogeneity observed in our patients supports the notion of genetic heterogeneity in the HSS/NBIA syndrome.

Adolescent↗
PubMed2004

Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration.

Mutations in the pantothenate kinase 2 gene (PANK2) lead to pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome). This neurodegenerative disorder is characterized by iron accumulation in the basal ganglia. Pantothenate kinase is the first enzyme in the biosynthesis of coenzyme A from pantothenate (vitamin B(5)). PANK2, one of four human pantothenate kinase genes, is uniquely predicted to be targeted to mitochondria. We demonstrate mitochondrial localization of PANK2 and speculate on mechanisms of secondary iron accumulation in PKAN. Furthermore, PANK2 uses an unconventional translational start codon, CUG, which is polymorphic in the general population. The variant sequence, CAG (allele frequency: 0.05), leads to skipping of the mitochondrial targeting signal and cytosolic localization of PANK2. This common variant may cause mitochondrial dysfunction and impart susceptibility to late-onset neurodegenerative disorders with brain iron accumulation, including Parkinson's disease.

Animals↗
PubMed2003

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.

Age of Onset↗
PubMed2003

Progressive dystonia in a 12-year-old boy.

Pantothenate kinase-associated neurodegeneration (PKAN) (MIM 234200; Hallervorden-Spatz syndrome) is a degenerative, autosomal recessive disorder in childhood, currently without specific treatment. In contrast to variable clinical features, T2-weighted magnetic resonance images show a characteristic 'eye-of-the-tiger sign' in the globus pallidus due to excess iron deposition. Recently a defect in pantothenate kinase, the key regulatory enzyme in the synthesis of coenzyme A from pantothenate, has been identified as the cause of the disease. We report a 12-year-old boy with progressive rigidity, dystonia, impaired voluntary movement, dysarthria, and mental deterioration. Over 10 years the boy had been misdiagnosed with clumsiness, emotional and behavioural deficits, and attention deficit disorder, before neuroimaging was performed showing the characteristic 'eye-of-the-tiger sign'. Molecular analyses confirmed two mutations in the PANK2 gene [coding sequence of a gene that has homology to murine pantothenate kinase-1]. We conclude that in progressive childhood dystonia, PKAN should be considered and magnetic resonance imaging performed early. The newly described defect of the pantothenate kinase enzyme enables a novel therapeutic approach to be considered, based on the mutation analyses of the PANK2 gene, as well as the prenatal diagnosis of this disorder.

Child↗