Aceruloplasminemia presents as Type 1 diabetes in non-obese adults: a detailed case series.

AIM: To detect features that might lead to the early diagnosis and treatment of aceruloplasminemia, as initiation of treatment before the onset of neurological symptoms is likely to prevent neurological deterioration. METHODS: The PubMed and OMIM databases were searched for published cases of aceruloplasminemia. Diagnostic criteria for aceruloplasminemia were undetectable or very low serum ceruloplasmin, hyperferritinemia and low transferrin saturation. Clinical, biochemical and radiological data on the presentation and follow-up of the cases were extracted and completed through e-mail contact with all authors. RESULTS: We present an overview of 55 aceruloplasminemia cases, including three previously unreported cases. Diabetes mellitus was the first symptom related to aceruloplasminemia in 68.5% of the patients, manifesting at a median age of 38.5 years, and often accompanied by microcytic or normocytic anaemia. The combination preceded neurological symptoms in almost 90% of the neurologically symptomatic patients and was found 12.5 years before the onset of neurological symptoms. CONCLUSIONS: There is a diagnostic window during which diabetes and anaemia are present although there is an absence of neurological symptoms. Screening for aceruloplasminemia in adult non-obese individuals presenting with antibody-negative, insulin-dependent diabetes mellitus and unexplained anaemia is recommended. The combination of ferritin and transferrin saturation provides a sensitive initial measure for aceruloplasminemia.

Recent advances in progressive supranuclear palsy: a review.

Progressive Supranuclear Palsy has been used over decades as a term denoting an uniform disorder with progressive parkinsonism with early falls, vertical supranulcear gaze palsy, pseudobulbar dysfunction and cognitive decline. Over the last decade, heterogeneity of the disease into different clinical subtypes has been recognized in clinicopathological studies. Although neuroimaging features and laboratory findings may support the diagnosis, true biomarkers are still lacking in the clinical setting. Neuronal and glial tau positive aggregates are predominantly found in basal ganglia and brainstem, and the significant association of PSP with the common H1 tau haplotype likely points to a pathophysiological role of the tau protein in the disease process. Future genetic studies of familial cases and an ongoing genome-wide association study of large series of pathological-proven cases may reveal additional genetic factors in the near future.

Familial aggregation of parkinsonism in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age- and sex-matched control group. METHODS: Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age- and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases. RESULTS: Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99-7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas. CONCLUSION: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy.

Frontal presentation in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive hypokinetic rigid disorder with supranuclear gaze palsy and frequent falls. Although clinical consensus criteria are available, an atypical presentation may lead to clinical misdiagnosis in the initial phase. In the present study we investigated the clinical presentation of PSP and its relationship to initial clinical diagnosis and survival. METHODS: We ascertained patients with PSP in a prospective cohort by nationwide referral from neurologists and nursing home physicians. All patients underwent a structural interview and clinical examination before entering the study. Medical records were reviewed for the presence of symptoms during the first 2 years. RESULTS: A total of 152 patients ascertained between 2002 and 2005 fulfilled the international consensus criteria for PSP. Categorical principal component analysis of clinical symptoms within the first 2 years showed apart from a cluster of typical PSP symptoms, the clustering of cognitive dysfunction and behavioral changes. Further analysis showed that 20% of patients had a predominant frontal presentation with less than two other PSP symptoms. Survival analysis showed that this subgroup had a similar prognosis to that of the total group of patients with PSP. CONCLUSIONS: There exists a subgroup of patients with progressive supranuclear palsy (PSP) with a predominant frontal presentation, who progressed into typical PSP over the course of the disease.

How to select patients with normal pressure hydrocephalus for shunting.

The objective was to compare predictive values of clinical and CT findings, co-existing cerebrovascular disease (CVD) and CSF outflow resistance (Rcsf) for outcome of shunting in NPH. A group of 95 NPH patients was shunted and followed for one year. Gait disturbance and dementia were quantified by an NPH scale (NPHS) and handicap by the modified Rankin scale (MRS). Improvement was defined as a change of at least 15% in NPHS and one grade in MRS at last follow-up. Clinical and CT findings at entry were classified as typical or not typical for NPH. CVD was defined as a history of stroke or CT-scans showing infarcts or moderate to severe white matter hypodense lesions. Clinical and CT findings typical for NPH, absence of CVD and Rcsf > 18 mmHg/ml/min were positive tests and the reciprocal outcomes negative tests. Typical clinical and CT findings were found in 69% and 68%, CVD (history of stroke n = 14, infarcts on CT n = 13, leucoaraiosis n = 32) in 47% and Rcsf > 18 in 38% of patients. The ratio of patients classified as improved in both scales was significantly greater for those with positive than negative tests. Mean improvement differed the most between patients with and without CVD. Using logistic regression analysis Rcsf > 18 was the only significant predictor of improvement in NPHS (OR 4.4, 95% CI 1.3-16.7) and typical CT findings in MRS (OR 5.6, 95% CI 1.8-17.9). We conclude that CVD is an important predictor of poor outcome. The best strategy is to shunt NPH patients if Rcsf is > 18 mmHg/ml/min or, when Rcsf is lower, if CT findings are typical for NPH and there is no or limited CVD.

Cerebral hemodynamics before and after shunting in normal pressure hydrocephalus.

OBJECTIVE: To study the relationship between cerebral hemodynamics and clinical performance in normal pressure hydrocephalus (NPH), before and after surgery. MATERIAL AND METHODS: Ten patients were studied prospectively before and 3 months after shunt surgery by means of transcranial Doppler (TCD). Clinical performance was scored by means of an NPH scale and the modified Rankin scale. RESULTS: Peak systolic and mean cerebral blood flow velocity (MCV) were lower and cerebrovascular CO2 reactivity was higher after shunt surgery. The three patients with clinical improvement had higher preoperative end diastolic cerebral blood flow velocity and MCV. All postoperative cerebral blood flow velocities were higher in patients with clinical improvement. CONCLUSION: Our data suggest that higher cerebral blood flow velocity before surgery in patients with NPH is related to clinical improvement after shunt surgery. Cerebral hemodynamic parameters may develop into predictors of successful shunt surgery in patients with normal pressure hydrocephalus.