Psychometric outcome measures in beta-propeller protein-associated neurodegeneration (BPAN).

BACKGROUND: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder characterized by iron accumulation in the brain with spectrum of neurodevelopmental and movement phenotypes. In anticipation of future clinical trials and to inform clinical care, there is an unmet need to capture the phenotypic diversity of this rare disorder and better define disease subtypes. METHODS: A total of 27 individuals with BPAN were included in our natural history study, from which traditional outcome measures were obtained in 18 subjects. Demographic and diagnostic information, along with acquisition of basic developmental skills and overall neurologic severity were extracted from the medical records. Functional outcome measures were administered at the time of the evaluation or applied retrospectively at the last clinical encounter for patients who were not able to travel for in person. Based on age and functional level, the following assessments were administered: Leiter-3, Gross Motor Function Measure (GMFM)-66 Item Sets, Vineland-3, and Peabody-2. RESULTS: Overall, cognitive function was more impaired compared to gross motor function. Onset of symptoms of BPAN within the first 6 months of life was associated with decreased gain of ambulation and gain of spoken language (ambulation: log-rank test p = 0.0015; gain of first word: p = 0.0015). There was no difference in age at seizure onset by age at initial symptom onset (p = 0.8823). Collection of prospective outcome measures was limited by attention and behavior in our patient population, reinforcing the complexity of phenotype assessment and inadequacy of available standardized tests. Overall, gross motor and adaptive behavior assessments were better able to capture the dynamic range of function across the BPAN population than the fine motor and non-verbal cognitive tests. Floor effects were noted across outcome measures in a subset of individuals for cognitive and adaptive behavior tests. CONCLUSION: Our data suggest the distinct phenotypes of BPAN: a severe, early onset form and an attenuated form with higher cognitive capabilities. Early age at onset was a key factor in predicting future neurologic impairment.

Ferritin L-subunit gene mutation and hereditary hyperferritinaemia cataract syndrome (HHCS): a case report and literature review.

ABSTRACTObjectives: Hereditary hyperferritinaemia cataract syndrome (HHCS) is an autosomal dominant disease characterized by high serum ferritin levels and juvenile bilateral cataracts. It is often caused by mutations in the iron response element (IRE) of the ferritin L-subunit (FTL) gene. Here, we report a 73-year-old woman who presented to clinic with persistently elevated serum ferritin and family history of juvenile bilateral cataracts in four generations.Methods: Exome sequencing was used to identify the mutation of the FTL gene. Moreover, Sanger sequencing was performed to validate the mutation in the proband. We also reviewed the FLT gene mutations in published HHCS cases to provide experience for accurate diagnosis of similar patients.Results: A heterozygous mutation at position +33 (c.-167C > T, chr19:49468598) of the FTL gene was identified in the patient.Discussion: HHCS should be considered in the differential diagnosis of hyperferritinemia, especially in the presence of normal serum iron concentration and transferrin saturation.Conclusion: For patients with unexplained hyperferritinemia and bilateral cataracts who have experienced early vision loss, the establishment of genetic counseling is essential to diagnose other family members who are at risk in time.Abbreviations: FTL: ferritin L-subunit; HHCS: hereditary hyperferritinaemia cataract syndrome; IDT: integrated DNA technologies; IRE: iron response element; IRP: iron regulatory proteins; MRI: magnetic resonance imaging; SNV: single nucleotide variant; UTR: untranslated region.

A novel ceruloplasmin mutation identified in a Chinese patient and clinical spectrum of aceruloplasminemia patients.

Aceruloplasminemia (ACP) is a rare disorder of iron overload resulting from ceruloplasmin (CP) variants. Because of its rarity and heterogeneity, the diagnosis of ACP is often missed or misdiagnosed. Here, we aim to present a clinical spectrum of ACP and raise more attention to the early diagnosis. Whole exome sequencing (WES) was performed in a Chinese female patient suspected with ACP and her clinical data were collected in detail. The PubMed databases was searched for published ACP patients within the last decade, and we present a systematic review of their clinical features with data extracted from these researches. A novel pathogenic variant (c.2689delC) and a known pathogenic variant (c.606dupA) within ceruloplasmin gene were identified in our patient and confirmed the diagnosis of ACP. Then we reviewed 51 ACP patients including the case we reported here. A possible timeline of symptoms was discovered, anemia appears first (29.7 years old on average), followed by diabetes (37.3 years old) and finally neurological symptoms (50.7 years old). The delay in diagnosis was significantly shortened in patients without neurological symptoms. Biochemical triad including anemia, low to undetectable serum ceruloplasmin, low serum iron and/or hyperferritinemia, showed better sensitivity in diagnosis than clinical triad including diabetes, neurological symptoms, and retinal degeneration. Due to the variable symptom spectrum, patients with ACP often visit different departments, which can lead to misdiagnosis. Clinical attention needs to be paid to symptoms and tests that have a warning effect. Prompt diagnosis in the early stage of the disease can be beneficial.

Neurodegeneration with brain iron accumulation: Characterization of clinical, radiological, and genetic features of pediatric patients from Southern India.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) is a group of rare inherited neurodegenerative disorders. Ten types of NBIA are known. Studies reporting various NBIA subtypes together are few. This study was aimed at describing clinical features, neuroimaging findings, and genetic mutations of different NBIA group disorders. METHODS: Clinical, radiological, and genetic data of patients diagnosed with NBIA in a tertiary care centre in Southern India from 2014 to 2020 was retrospectively collected and analysed. RESULTS: In our cohort of 27 cases, PLA2G6-associated neurodegeneration (PLAN) was most common (n = 13) followed by Pantothenate kinase-associated neurodegeneration (PKAN) (n = 9). We had 2 cases each of Mitochondrial membrane-associated neurodegeneration (MPAN) and Beta-propeller protein- associated neurodegeneration (BPAN) and 1 case of Kufor-Rakeb Syndrome (KRS). Walking difficulty was the presenting complaint in all PKAN cases, whereas the presentation in PLAN was that of development regression with onset at a mean age of 2 years. Overall, 50% patients of them presented with development regression and one-third had epilepsy. Presence of pyramidal signs was most common examination feature (89%) followed by one or more eye findings (81%) and movement disorders (50%). Neuroimaging was abnormal in 24/27 cases and cerebellar atrophy was the commonest finding (52%) followed by globus pallidus hypointensities (44%). CONCLUSIONS: One should have a high index of clinical suspicion for the diagnosis of NBIA in children presenting with neuroregression and vision abnormalities in presence of pyramidal signs or movement disorders. Neuroimaging and ophthalmological evaluation provide important clues to diagnosis in NBIA syndromes.

Abnormal iron status is associated with an increased risk of mortality in patients on peritoneal dialysis.

BACKGROUND AND AIMS: Iron deficiency is prevalent, but there is limited data about the relationship between iron status and poor outcomes in chronic kidney disease patients undergoing peritoneal dialysis (PD). We aimed to investigate the association between iron status and mortality in PD patients. METHODS AND RESULTS: This retrospective study was conducted on incident PD patients from January 2006 to December 2016 and followed up until December 2018. Patients were categorized into four groups according to baseline serum transferrin saturation (percent) and ferritin levels (ng/ml): reference (20-30%, 100-500 ng/ml), absolute iron deficiency (<20%, <100 ng/ml), function iron deficiency (FID) (<20%, >100 ng/ml), and high iron (>30%, >500 ng/ml). Among the 1173 patients, 77.5% had iron deficiency. During a median follow-up period of 43.7 months, compared with the reference group, the FID group was associated with increased risk for all-cause [adjusted hazard ratio (aHR) 1.87, 95% confidence interval (95% CI) 1.05-3.31, P = 0.032], but not cardiovascular (CV) mortality. Additionally, the high iron group had a more than four-fold increased risk of both all-cause and CV mortality [aHR 4.32 (95% CI 1.90-9.81), P < 0.001; aHR 4.41 (95% CI 1.47-13.27), P = 0.008; respectively]. CONCLUSION: FID and high iron predict worse prognosis of patients on PD.

A 3'-truncating FTL mutation associated with hypoferritinemia without neuroferritinopathy.

Mutations in the gene for the ferritin light chain (FTL) often present with hypoferritinemia associated with progressive, late onset extrapyramidal dysfunction. However, it has been suggested that some FTL mutations may impact ferritin levels without any neurological manifestations. We report on a FTL mutation in a three generation family with autosomal dominant hypoferritinemia without neurodegeneration. The 4 year old proband was identified with longstanding history of hypoferritinemia without evidence of anemia. Brain MRI did not show any evidence of iron deposition. It was found that the patient's 19 month old sister, 30 year old mother and 58 year old maternal grandmother also had hypoferritinemia and normal iron levels. Over the next nine years, none of these persons had any evidence of neurological dysfunction, including movement disorders, gait disturbances, behavioral or psychiatric dysfunction. Whole exome sequencing revealed a heterozygous interstitial deletion of at least 5 kb within cytogenic band 19q13.33 involving exons 3 and 4 of FTL in all affected family members. This 3' FTL deletion is predicted to create a significantly truncated protein product. We conclude that haploinsufficiency of FTL may be associated with hypoferritinemia without neurological dysfunction.

Dominant mitochondrial membrane protein-associated neurodegeneration (MPAN) variants cluster within a specific C19orf12 isoform.

Mitochondria membrane protein-associated neurodegeneration (MPAN) neurodegenerative disorder is typically associated with biallelic C19orf12 variants. Here we describe a new and review candidate previous monoallelic de novo C19orf12 variants to define loss of function mutations located in the putative non-membrane spanning C19orf12 isoform as the potential basis of monoallelic MPAN.

BPAN manifesting with febrile seizures and language delay: a case report from Brazil

Neurodegeneration with brain iron accumulation (NBIA) is a complex group of hereditary progressive neurodegenerative diseases characterized by deposition of iron in the basal ganglia. Twelve genetic forms of this disorder have been identified in previous studies. Though they have different inheritance mechanisms all are usually associated with abnormal brain MRI findings. One of NBIA types is an X-linked disorder known as Beta-propeller Protein Associated Neurodegeneration (BPAN). Herein we describe the case of a 4-year-old girl with 2 episodes of febrile seizures, a brain MRI showing nonspecific hyperintense signal in the dentate nucleus area, and delays in language and communication development. Her diagnosis was made based on a genetic evaluation where exome sequencing revealed a mutation in the position chrX:48.933.022 region of the WDR45 gene. The literature describes different clinical presentations for BPAN, each with a different prognosis, suggesting a wide range of possible symptoms of BPAN, including mild cognitive delay and even epileptic encephalopathy (EE). (AU)

Hyperferritinaemia-cataract syndrome. / Hyperferritinemi-katarakt-syndrom.

BACKGROUND: Elevated serum ferritin levels are common findings in clinical practice, usually caused by inflammation, liver disease, high alcohol consumption or malignancy, although it can occur in association with rare genetic conditions. CASE PRESENTATION: We describe a male in his sixties with persistent hyperferritinaemia without associated iron overload and subsequent development of cataract. The patient himself suggested hyperferritinaemia-cataract syndrome as a diagnosis, which was subsequently confirmed with mutation analysis of the light chain ferritin (FTL) gene. Such mutations are inherited in an autosomal dominant pattern. INTERPRETATION: Mutations in FTL are known to interfere with the balance between iron levels and ferritin production. When common causes of hyperferritinaemia are excluded, rare conditions should be considered in order to avoid unnecessary procedures and treatment. Genetic analyses are available for all clinicians and should be requested upon the right indications.

Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares.

BACKGROUND: Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited. CASE PRESENTATION: We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264_269delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636 + 2 T > A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. CONCLUSIONS: Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.

Is there heart disease in cases of neurodegeneration associated with mutations in C19orf12?

INTRODUCTION: In mitochondrial membrane protein-associated neurodegeneration (MPAN), a subtype of neurodegeneration with brain iron accumulation (NBIA), patients suffer from optic nerve atrophy and dementia, which are also typical for another group of diseases, the mitochondrial diseases (MD). Around 30% of patients with MD have heart disease, commonly cardiomyopathy and arrhythmias, and 10% experience a major adverse cardiovascular event. The aim of this study was to assess cardiac involvement in MPAN. METHODS: Thirteen patients with MPAN were evaluated after written informed consent. All patients had echocardiography and 12 patients had 24-h Holter electrocardiogram (ECG) monitoring using 3-channel digital recorders. RESULTS: Echocardiography revealed normal values for the dimensions of all heart chambers. The systolic function of the left ventricle was normal in all cases. Right ventricle systolic impairment was found in three patients. 24-hour Holter ECG revealed predominant resting tachycardia during daytime with no physiological slowing of heart rate during sleep in seven cases. No significant arrhythmias were found. In nine patients, selected heart rate variability (HRV) parameters were lower than reference values. CONCLUSION: Cardiomyopathy, typical of MD, was not found in patients with MPAN. There were no significant arrhythmias, but disturbances in the circadian rhythm of the heart rate were observed in most cases. The decrease in HRV may reflect an early sign of autonomic dysfunction. A standard cardiac work-up is recommended for patients with MPAN to assess if additional treatment is needed.

[Aceruloplasminemia, a rare condition not to be overlooked]. / L'acéruléoplasminémie héréditaire, une pathologie à ne pas méconnaître.

Aceruloplasminemia is a rare iron-overload disease that should be better known by physicians. It is an autosomal recessive disorder due to mutations in ceruloplasmin gene causing systemic iron overload, including cerebral and liver parenchyma. The impairment of ferroxidase ceruloplasmin activity leads to intracellular iron retention leading aceruloplasminemia symptoms. Neurologic manifestations include cognitive impairment, ataxia, extrapyramidal syndrome, abnormal movements, and psychiatric-like syndromes. Physicians should search for aceruloplasminemia in several situations with high ferritin levels: microcytic anaemia, diabetes mellitus, neurological and psychiatric disorders. Diagnosis approach is based on the study of transferrin saturation and hepatic iron content evaluated by magnetic resonance imaging of the liver. Ceruloplasmin dosage is required in case of low transferrin saturation and high hepatic iron content and genetic testing is mandatory in case of serum ceruloplasmin defect. Neurological manifestations occur in the sixties decade and leads to disability. Iron chelators are widely used. Despite their efficacy on systemic and cerebral iron overload, iron chelators tolerance is poor. Early initiation of iron chelation therapy might prevent or slowdown neurodegeneration, highlighting the need for an early diagnosis but their clinical efficacy remains uncertain.

Investigations of Huntington's Disease and Huntington's Disease-Like Syndromes in Indian Choreatic Patients.

BACKGROUND: The diagnostic workup for choreiform movement disorders including Huntington's disease (HD) and those mimicking HD like phenotype is complex. OBJECTIVE: The aim of the present study was to genetically define HD and HD-like presentations in an Indian cohort. We also describe HTT-CAG expansion manifesting as neuroferritinopathy-like disorder in four families from Punjab in India. MATERIALS AND METHODS: 159 patients clinically diagnosed as HD and HD-like presentations from various tertiary neurology clinics were referred to our centre (CSIR-IGIB) for genetic investigations. As a first tier test, CAG-TNR for HTT was performed and subsequently HD-negative samples were screened for JPH3 (HDL2), TBP (SCA17), ATN1 (DRPLA), PPP2R2B (SCA12) and GGGGCC expansion in C9orf72 gene. Four families presenting as neuroferritinopathy-like disorder were also investigated for HTT-CAG expansion. RESULTS: 94 of 159 (59%) patients were found to have expanded HTT-CAG repeats. Pathogenic repeat expansion in JPH3, TBP, ATN1 and C9orf72 were not found in HD negative cases. Two patients were positive for SCA12-CAG expansion in pathogenic length, whereas 5 cases harboured TBP-CAG repeats falling in reduced penetrance range of 41- 48 repeats for SCA17. Four unrelated families, presented with atypical chorea and brain MRI findings suggestive of basal ganglia abnormalities mimicking neuroferritinopathy were found to harbour HTT-CAG expansion. CONCLUSION: We present SCA12 as a new reported phenocopy of HD which should be considered for diagnostic workout along with SCA17 for HD-like syndromes. This study also illustrates the necessity, to consider evolving HD like phenotype, as a clinical diagnosis for cases with initial manifestations depicting neuroferritinopathy.

Phenotypic and Imaging Spectrum Associated With WDR45.

BACKGROUND: Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5. Global developmental delay occurs at an early age with slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain. METHODS: We present 17 new cases and reviewed 106 reported cases of neurodegeneration with brain iron accumulation type 5. Detailed information related to developmental history and key time to event measures was collected. RESULTS: Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole-exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. Although most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted in half of our cohort and was associated with older age of image acquisition, whereas myelination abnormalities were associated with younger age. CONCLUSIONS: WDR45 mutations lead to a progressive and evolving disorder whose diagnosis is often delayed. Developmental delay and seizures predominate in early childhood, followed by a progressive decline of neurological function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation.

New mutation of the ceruloplasmin gene in the case of a neurologically asymptomatic patient with microcytic anaemia, obesity and supposed Wilson's disease.

BACKGROUND: Aceruloplasminaemia is a very rare autosomal recessive disorder caused by a mutation in the ceruloplasmin gene, which is clinically manifested by damage to the nervous system and retinal degeneration. This classical clinical picture can be preceded by diabetes mellitus and microcytic anaemia, which are considered to be early manifestations of aceruloplasminaemia. CASE PRESENTATION: In our report, we describe the case of a patient with aceruloplasminaemia detected in an early stage (without clinical symptoms of damage to the nervous system) during the search for the cause of hepatopathy with very low values of serum ceruloplasmin. Molecular genetic examination of the CP gene for ceruloplasmin identified a new variant c.1664G > A (p.Gly555Glu) in the homozygous state, which has not been published in the literature or population frequency databases to date. Throughout the 21-month duration of chelatase treatment, the patient, who is 43 years old, continues to be without neurological and psychiatric symptomatology. We observed a decrease in the serum concentration of ferritin without a reduction in iron deposits in the brain on magnetic resonance imaging. CONCLUSION: Currently, there is no unequivocal recommendation of an effective treatment for aceruloplasminaemia. Early diagnosis is important in the neurologically asymptomatic stage.

Genetic and Clinical Heterogeneity in Thirteen New Cases with Aceruloplasminemia. Atypical Anemia as a Clue for an Early Diagnosis.

Aceruloplasminemia is a rare autosomal recessive genetic disease characterized by mild microcytic anemia, diabetes, retinopathy, liver disease, and progressive neurological symptoms due to iron accumulation in pancreas, retina, liver, and brain. The disease is caused by mutations in the Ceruloplasmin (CP) gene that produce a strong reduction or absence of ceruloplasmin ferroxidase activity, leading to an impairment of iron metabolism. Most patients described so far are from Japan. Prompt diagnosis and therapy are crucial to prevent neurological complications since, once established, they are usually irreversible. Here, we describe the largest series of non-Japanese patients with aceruloplasminemia published so far, including 13 individuals from 11 families carrying 13 mutations in the CP gene (7 missense, 3 frameshifts, and 3 splicing mutations), 10 of which are novel. All missense mutations were studied by computational modeling. Clinical manifestations were heterogeneous, but anemia, often but not necessarily microcytic, was frequently the earliest one. This study confirms the clinical and genetic heterogeneity of aceruloplasminemia, a disease expected to be increasingly diagnosed in the Next-Generation Sequencing (NGS) era. Unexplained anemia with low transferrin saturation and high ferritin levels without inflammation should prompt the suspicion of aceruloplasminemia, which can be easily confirmed by low serum ceruloplasmin levels. Collaborative joint efforts are needed to better understand the pathophysiology of this potentially disabling disease.

Early-onset presentation of a new subtype of ß-Propeller protein-associated neurodegeneration (BPAN) caused by a de novo WDR45 deletion in a 6 year-old female patient.

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare genetic disorders characterized by progressive extrapyramidal and other neurological symptoms due to focal iron accumulation in the basal ganglia (Adidi et al., 2016). ß-Propeller protein-associated neurodegeneration (BPAN) is the most recently identified subtype of NBIA caused by heterozygous variants in WDR45 (OMIM: *300526) at Xp11.23. We report the clinical neurophysiological and neuro-imaging findings of a new subtype of BPAN in a 6 year-old female patient, who was identified to have a large de novo WDR45 deletion who presented in the first year of life with early onset global developmental delay, severe cognitive impairment, generalized hypotonia and a corticosteroid responsive epileptic encephalopathy.