Magnetic resonance imaging and spectroscopy in late-onset GM2-gangliosidosis.

OBJECTIVE: Our study aimed to quantify structural changes in relation to metabolic abnormalities in the cerebellum, thalamus, and parietal cortex of patients with late-onset GM2-gangliosidosis (LOGG), which encompasses late-onset Tay-Sachs disease (LOTS) and Sandhoff disease (LOSD). METHODS: We enrolled 10 patients with LOGG (7 LOTS, 3 LOSD) who underwent a neurological assessment battery and 7 age-matched controls. Structural MRI and MRS were performed on a 3 T scanner. Structural volumes were obtained from FreeSurfer and normalized by total intracranial volume. Quantified metabolites included N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), and combined glutamate-glutamine (Glx). Metabolic concentrations were corrected for partial volume effects. RESULTS: Structural analyses revealed significant cerebellar atrophy in the LOGG cohort, which was primarily driven by LOTS patients. NAA was lower and mI higher in LOGG, but this was also significantly driven by the LOTS patients. Clinical ataxia deficits (via the Scale for the Assessment and Rating of Ataxia) were associated with neuronal injury (via NAA), neuroinflammation (via mI), and volumetric atrophy in the cerebellum. INTERPRETATION: The decrease of NAA in the cerebellum suggests that, in addition to cerebellar atrophy, there is ongoing impaired neuronal function and/or loss, while an increase in mI indicates possible neuroinflammation in LOGG (more so within the LOTS subvariant). Quantifying cerebellar atrophy in relation to neurometabolic differences in LOGG may lead to improvements in assessing disease severity, progression, and pharmacological efficacy. Lastly, additional neuroimaging studies in LOGG are required to contrast LOTS and LOSD more accurately.

Late-onset epilepsy and 25-year cognitive change: The Atherosclerosis Risk in Communities (ARIC) study.

OBJECTIVE: To define the association between late-onset epilepsy (LOE) and 25-year change in cognitive performance. METHODS: The Atherosclerosis Risk in Communities (ARIC) study is a multicenter longitudinal cohort study with participants from four U.S. communities. From linked Medicare claims, we identified cases of LOE, defined as ≥2 seizure-related diagnostic codes starting at age ≥67. The ARIC cohort underwent evaluation with in-person visits at intervals of 3-15 years. Cognition was evaluated 4 times over >25 years (including before the onset of seizures) using the Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT); a global z-score was also calculated. We compared the longitudinal cognitive changes of participants with and without LOE, adjusting for demographics and LOE risk factors. RESULTS: From 8033 ARIC participants with midlife cognitive testing and Medicare claims data available (4523 [56%] female, 1392 [17%] Black), we identified 585 cases of LOE. The rate of cognitive decline was increased on all measures in the participants who developed LOE compared to those without LOE. On the measure of global cognition, participants with LOE declined by -0.43 z-score points more over 25 years than did participants without epilepsy (95% confidence interval [CI] -0.59 to -0.27). Prior to the onset of seizures, cognitive decline was more rapid on the DWRT, DSST, and global z-scores in those who would later develop LOE than it was in non-LOE participants. Results were similar after excluding data from participants with dementia. SIGNIFICANCE: Global cognition, verbal memory, executive function, and word fluency declined faster over time in persons developing LOE than without LOE. Declines in cognition preceding LOE suggest these are linked; it will be important to investigate causes for midlife cognitive declines associated with LOE.

Nonlesional late-onset epilepsy: Semiology, EEG, cerebrospinal fluid, and seizure outcome characteristics.

INTRODUCTION: Incidence and prevalence of epilepsy increase with advancing age. Although the majority of late-onset epilepsies are of lesional origin, a considerable proportion of patients present with unknown etiology. The aim of this study was to evaluate the semiological, electroencephalographic (EEG), and cerebrospinal fluid (CSF) characteristics as well as the 12-month seizure outcome in a cohort of patients with nonlesional late-onset epilepsy (≥55 years). METHOD: A total of 54 patients with newly diagnosed nonlesional late-onset epilepsy (NLLOE) were retrospectively evaluated for seizure type using the most recent International League Against Epilepsy (ILAE) classification of seizure types, EEG characteristics, and CSF profile and followed-up for at least 12 months after epilepsy onset. Results were compared with a gender-matched control group of 58 patients with nonlesional early-onset epilepsy (NLEOE). RESULTS: The predominant seizure types in NLLOE were focal to bilateral tonic-clonic seizures (30%) as well as focal onset impaired awareness motor seizures (IAMS) (22%) and focal onset impaired awareness nonmotor seizures (IANMS) (22%). The predominant seizure types in NLEOE were focal to bilateral tonic-clonic seizures (43%) as well as focal onset aware nonmotor seizures (ANMS) (31%) and IAMS (31%). Focal onset impaired awareness nonmotor seizures were found to be more characteristic in patients with NLLOE (p = 0.019; α < 0.05; NLLOE: 22.2% vs. NLEOE: 8.6%). Electroencephalography revealed no significant differences between groups. Of interest, three patients with NLLOE (8%) presented with oligoclonal bands (OCB) in CSF albeit absence of antineuronal antibodies. Seizure-free rate was 70%. Adverse effects from medication leading to antiepileptic drug (AED) change were reported in 12 patients (22%), valproate was the best tolerated AED in patients with NLLOE [adverse effects in 9%, compared with 12% (gabapentin) and 26% (levetiracetam)]. CONCLUSIONS: Using the most recent classification system, different patterns of semiological characteristics were identified: NLLOE more frequently present with IANMS, whereas patients with NLEOE rather have ANMS. Oligoclonal bands were only detected in patients with NLLOE, indicating that careful exclusion of autoimmune encephalitis in this patient group is warranted. Our findings may help to more accurately identify and characterize patients with NLLOE to improve targeted diagnostics and adequate treatment in this challenging group of patients.

Late-onset night blindness with peripheral flecks accompanied by progressive trickle-like macular degeneration.

PURPOSE: To report the clinical and genetic characteristics of 6 cases with late-onset night blindness with peripheral flecks accompanied by progressive trickle-like macular degeneration. METHODS: Clinical and genetic data were collected from 6 independent patients who complained of night blindness in their fifth to eighth decade of life. The ophthalmological examinations included ophthalmoscopy, fundus autofluorescence (FAF), and full-field electroretinography (ERG). Whole exome sequencing with target gene analysis was performed to determine the causative genes and variants. RESULTS: All of the patients first complained of night blindness at the ages of 40-71 years. Funduscopic examinations demonstrated white or atrophic flecks scattered in the posterior pole and peripheral retina bilaterally. FAF showed patchy hypo-autofluorescence spots in the posterior pole similar to that of the trickling type of age-related macular degeneration (AMD). The region of abnormal FAF rapidly expanded with age, and one eye developed a choroidal neovascularization. The full-field scotopic ERGs with 20 min of dark adaptation were severely reduced or extinguished in all cases. There was partial recovery of the ERGs after 180 min of dark adaptation. The cone ERGs were reduced in all cases. Whole exome sequencing revealed no pathogenic variants of 301 retinal disease-associated genes. CONCLUSIONS: The six cases had some common features with the flecked retina syndrome, familial drusen, and late-onset retinal degeneration although none had pathogenic variants causative for these disorders. These cases may represent a subset of severe trickling AMD or a new clinical entity of acquired pan-retinal visual cycle deficiency of unknown etiology.

When rejuvenation is a problem: challenges of modeling late-onset neurodegenerative disease.

In contrast to the successful modeling of early-onset disorders using patient-specific cells, modeling of late-onset neurodegenerative diseases such as Parkinson's disease remains a challenge. This might be related to the often ignored fact that current induced pluripotent stem cell (iPSC) differentiation protocols yield cells that typically show the behavior of fetal stage cells. Acknowledging aging as a contributing factor in late-onset neurodegenerative disorders represents an important step on the road towards faithfully recreating these diseases in vitro. Here, we summarize progress in the field and review the strategies and challenges for triggering late-onset disease phenotypes.

Age-Related Hearing Loss and Its Association with Depression in Later Life.

OBJECTIVES: To evaluate the association between age-related hearing loss (ARHL) and depressive symptoms in older adults over time. METHODS: Data from the Health Aging and Body Composition study (N = 3075, aged 70-79 at baseline) were used previously to conduct a longitudinal latent class analysis to evaluate depression trajectories (Center for Epidemiologic Studies Depression [CES-D] Scale) over 10 years. Restricting to the subset of subjects who had hearing information available (N = 1204), self-reported hearing categories were evaluated over the same period. Association between depression classes and hearing categories were assessed via multinomial logistic regression analyses. Correlation analyses and two-sample t-tests were used to assess cross-sectional associations between depression status and audiometric hearing measures. RESULTS: Low-probability (N = 644), increasing-probability (N = 385), and high-probability (N = 175) trajectories of depressive symptoms were identified for the 10-year period. Impaired/Worsening (N = 182) and Healthy/Improving (N = 1,022) hearing categories were defined using self-reports. With the low-probability depression trajectory as the reference group, subjects reporting Impaired/Worsening hearing had 1.63 times increased odds of having an increasing- (p = 0.0088, 95% CI [1.13, 2.34]) and 1.85 times increased odds of having a high-probability depression trajectory (p = 0.0102, 95% CI [1.16, 2.96]). At Year 5, individuals with depressive symptoms (10CES-D ≥ 10) had impaired hearing ability measured by audiometric threshold for low-frequency (Adjusted mean difference = 2.29 dBHL, p = 0.0005) and mid-frequency sounds (Adjusted mean difference = 2.28 dBHL,p = 0.0049) compared to those with 10CES-D < 10. CONCLUSIONS: ARHL was associated with increased depressive symptoms in older adults. Future studies should investigate whether treatment of ARHL may be an effective prevention and/or therapeutic strategy for depressive symptoms.

Symptomatic and Functional Recovery From Major Depressive Disorder in the Ibadan Study of Ageing.

OBJECTIVES: Very little is known about the association between symptomatic and functional recovery from late-life major depressive disorder (MDD) in sub-Saharan Africa. We investigated factors associated with sustained symptomatic remission (SR) from MDD and the 5-year trajectory of post-MDD physical functioning. DESIGN: 5-year prospective study with three follow-up waves in 2007, 2008, and 2009. SETTING/PARTICIPANTS: Household multistage probability sample of 2,149 Nigerians who were aged 65 years or older. MEASUREMENTS: Activities of Daily Living (ADL) and MDD were assessed using the Kadz index and Composite International Diagnostic Interview, respectively. We studied those with current MDD (prevalent in 2003-2004 or incident in 2007), and who achieved SR in subsequent waves compared with a chronic/recurrent course (CR). RESULTS: Baseline demographic characteristics, health, and lifestyle factors were not associated with SR in logistic regression analyses. In mixed-effect linear regression models adjusting for age, sex, and socioeconomic status, ADL worsened in SR (ß = 1.0, 95% CI: 0.2, 1.8), but more so in CR (ß = 2.3, 95% CI: 1.6, 3.0). Poorer ADL at follow-up was predicted by age (ß = 2.9, 95% CI: 1.8, 4.0) and economic status (ß = 1.4, 95% CI: 0.3, 2.4). CONCLUSIONS: There was a deteriorating course of disability despite symptomatic recovery from late-life MDD in this sample. This finding has implications for policy and guidelines for the management of late-life depression and disability.

Head-drop: A frequent feature of late-onset myasthenia gravis.

INTRODUCTION: Head-drop is often encountered in myasthenia gravis (MG) patients, but its frequency and clinical course have not been studied systematically. METHODS: In a retrospective study of a cohort of MG patients seen over a period of 11 years in a tertiary medical center, we assessed the clinical characteristics of patients who had head-drop. RESULTS: Of 146 generalized MG patients, 15 had head-drop during the course of their disease. Head-drop patients had older age of onset than those who did not have head-drop (mean age of onset 59.1 vs. 42.3 years) and were predominantly men. Head-drop was present in 23% of patients > 60 versus 6% of those < 60 years, and it improved in 9 of 11 patients with treatment directed to generalized MG. CONCLUSIONS: Head-drop is a common, treatment-responsive manifestation of late-onset MG. Muscle Nerve 56: 441-444, 2017.

Late-Life Depression: Modifications of Brain Resting State Activity.

Late-life depression (LLD) is a common emotional and mental disability in the elderly population characterized by the presence of depressed mood, the loss of interest or pleasure in daily activities, and other depression symptoms. It has a serious effect on the quality of life of elderly individuals and increases their risk of developing physical and mental diseases. It is an important area of research, given the growing elderly population. Brain functional connectivity modifications represent one of the neurobiological biomarker for LLD even if to date remains poorly understood. In our study, we enrolled 10 elderly patients with depressive symptoms compared to 11 age-matched healthy controls. All participants were evaluated by means of neuropsychological tests and underwent the same functional magnetic resonance imaging (fMRI) protocol to evaluate modifications of brain resting state functional connectivity. Between-group differences were observed for the Geriatric Depression Scale and Hamilton Depression Rating Scale, with higher scores for patients with LLD. Voxel-wise, 1-way analysis of variance revealed between-group differences in left frontoparietal network (lFPN) and sensory motor network (SMN): Increased intrinsic connectivity in the LLD group was observed in the left dorsolateral prefrontal cortex and in the left superior parietal lobule of the lFPN and increased intrinsic connectivity in the LLD group was observed in the bilateral primary somatosensory cortex of the SMN. Our findings support the use of resting state fMRI as a potential biomarker for LLD; even if to confirm the relationship between brain changes and the pathophysiology of LLD, longitudinal neuroimaging studies are required.

Early Elevation in Interleukin-6 is Associated with Reduced Growth in Extremely Low Birth Weight Infants.

Objective To determine whether reduced growth velocity (GV) in extremely low birth weight infants is preceded by elevated inflammatory cytokines. Study Design GV was determined at 36 weeks' postmenstrual age (PMA) in 768 infants 401 to 1,000 g birth weight (BW). Association between blood cytokines measured through day of life 21 and GV was explored using linear regression models that adjusted for late-onset sepsis (LOS), BW, small for gestational age (SGA), gender, race, energy intake, and center. Results Serum interleukin-6 (IL-6) was increased at days 14 and 21 in LOS infants. LOS was associated with reduced energy intake and GV for weight (weight-GV) at 36 weeks' PMA. Linear regression analysis controlling for LOS and energy intake showed significant relationships between increased IL-6 at days 14 and 21 with reduced weight-GV at 36 weeks' PMA (p < 0.0001). The relationship between day 21 IL-6 and weight-GV was not associated with LOS (p = 0.12) when controlling for BW and energy intake. Both BW (p = 0.02) and energy intake (p = 0.003) influenced the relationship between day 14 IL-6 and weight-GV. Conclusion IL-6 elevation during the first month of life is associated with lower weight-GV at 36 weeks' PMA and may have a direct effect upon energy balance and postnatal growth.

The Impact of Integrated Evaluation of Hemodynamics on Management of Preterm Infants with Late-Onset Compromised Systemic Circulation.

Objectives To study the impact of integrated evaluation of hemodynamics (IEH), using targeted neonatal echocardiography (TNE), cerebral regional tissue oxygenation (crRTO), and fractional oxygen extraction (FOE), using near-infrared spectroscopy (NIRS) on the management of infants with late-onset compromised systemic circulation (LCSC), and evaluation of the hemodynamic characteristics. Study Design Retrospective cohort study comparing infants with LCSC who underwent IEH (April 2014 to May 2016) with an earlier EPOCH who did not undergo IEH (January 2012 to March 2014). The primary outcome was the time to recovery. Results Total 43 infants were included; 18 infants underwent IEH with a median (IQR) 2 (1-3) assessments per infant. The time to recovery was shorter in IEH group with a median (IQR) 28 hours (15-62) compared with non-IEH group 96 hours (30-160). Autoregulation was compromised in 50%, and systemic vascular resistance (SVR) was low in 67%. Conclusion IEH was associated with shorter time to recovery in infants with LCSC.

Altered Functional Magnetic Resonance Imaging Markers of Affective Processing During Treatment of Late-Life Depression.

OBJECTIVE: This study investigated neural substrate changes in affective processing among late-life depression (LLD) patients undergoing antidepressant treatment and determined if these changes correlated with remission status. METHODS: Thirty-three LLD patients were enrolled in a 12-week venlafaxine treatment course. During treatment functional magnetic resonance imaging (fMRI) scans, paired with an affective task that assessed emotional reactivity and regulation, were performed on days 1, 2, 3, and 7 and at week 12. Following treatment patients were classified as remitters or non-remitters. A voxel-wise two-way repeated-measures ANOVA was performed to assess the fMRI data at a significance level of α = 0.05, corrected. RESULTS: The emotional reactivity contrast demonstrated a significant interaction between remission status and scan time in the right middle temporal gyrus (MTG) (F = 24.1, df = 1,112, k = 102). Further analysis showed increased emotional reactivity-induced activity among non-remitters, and decreased activity among remitters, which significantly differed from baseline at day 7 (95% CI: 0.027, 0.540; Cohen's d = -1.35) and week 12 (95% CI: -0.171, -0.052; Cohen's d = 0.68), respectively. No significant interaction was observed with the emotional regulation contrast, but multiple regions had significant main effects of scan time, including the cuneus, occipital lobe, insula, lingual gyrus, posterior cingulate cortex, and MTG. CONCLUSIONS: During treatment of LLD patients, affective processing-induced activity in the right MTG shows changes based on remission status. This alteration becomes evident early during the course of treatment, suggesting that antidepressant pharmacotherapy may acutely affect the neural basis of emotional reactivity in a differential manner that is relevant to illness remission.

Emotion Reactivity and Cerebrovascular Burden in Late-Life GAD: A Neuroimaging Study.

OBJECTIVE: Generalized anxiety disorder (GAD) in older adults is associated with persistent deficits in emotion reactivity (ER) and regulation, yet the neural basis of these deficits has not been explored. This study focuses on the neural basis of ER deficits in late-life GAD and the association with cerebrovascular burden. METHODS: Twenty elderly nonanxious participants and 17 late-life GAD participants were included. The faces-shapes functional magnetic resonance imaging task was used to assess ER; the Hamilton Anxiety Rating Scale and the Penn State Worry Questionnaire to measure global anxiety and worry, respectively; linear regression models to examine the association between ER and global anxiety severity and between ER and worry severity; and mediation analysis to explore the effect of ER on the relationship between global anxiety/worry severity and cerebrovascular burden. RESULTS: A positive association was found between ER and global anxiety in the left parahippocampus, left and right precuneus, and right superior occipital gyrus. A negative association was found between ER and worry severity in the left and right precuneus. The association between cerebrovascular burden and anxiety/worry severity was indirectly mediated by increased ER in limbic and paralimbic areas and by decreased ER in prefrontal regulatory regions. CONCLUSION: These results indicate that ER is associated with different neural activation patterns for worry and global anxiety and that ER-related functional connectivity indirectly mediates the relationship between cerebrovascular burden and late-life GAD. This latter result supports a yet-unexplored cerebrovascular pathway involved in the pathophysiology of late-life anxiety.

Inspiratory Muscle Training in Late-Onset Pompe Disease: The Effects on Pulmonary Function Tests, Quality of Life, and Sleep Quality.

INTRODUCTION: Late-onset Pompe disease (LOPD) is characterized by progressive skeletal and respiratory muscle weakness. Little is known about the effect of inspiratory muscle training (IMT) on pulmonary function in subjects with LOPD. The aim of the present study was to investigate the effect of an 8-week IMT program on pulmonary function tests, quality of life, and sleep quality in eight patients with LOPD who were receiving enzyme replacement therapy (ERT). METHODS: Before and after the IMT program, spirometric measurements in sitting and supine positions, and measurements of maximum inspiratory and expiratory pressures, peak cough flow, quality of life (assessed using the Nottingham Health Profile), and sleep quality (assessed using the Pittsburgh sleep quality index) were performed. RESULTS: A significant increase in maximum inspiratory pressure (cmH2O and % predicted) (median [interquartile range]: 30.0 cmH2O [21.5-48] versus 39 cmH2O [31.2-56.5] and 38.3 % [28.1-48.4] versus 50.5 % [37.7-54.9]) was observed after training (p = 0.01). There were no significant changes in the other pulmonary function measurements. With the exception of the social isolation subscore (p = 0.02), quality of life subscores did not change after IMT (p > 0.05). Sleep quality subscores and total scores were similar before and after IMT. CONCLUSION: These results suggest that IMT has a positive effect on maximum inspiratory pressure in subjects with LOPD who are under ERT.

Etiology and Long-Term Outcomes of Late-Onset Infantile Spasms.

OBJECTIVES: The purpose of the study was to evaluate the etiology and long-term outcomes of late-onset epileptic spasms (LOS). METHODS: This is a retrospective analysis of all consecutive patients seen at our center with onset of clusters of epileptic spasms between 1 and 3 years of age in 1995 through 2005. RESULTS: Overall, 17 children with LOS were identified. Overall, 14 children (82%) had structural etiology. Six patients received resective surgical treatment. Five had focal cortical dysplasia type 1 (FCD1) histology (29% of all the patients). Overall, 16 children were followed for 2 to 18 years. At the latest follow-up, seizure freedom was observed in 67% of the operated and in 50% of the nonoperated patients. Normal cognition or only mild mental deficiency was observed in nine patients (56%), of whom eight were seizure-free. All patients with intractable spasms had a severe mental deficiency. CONCLUSION: The overall cognitive outcome of LOS was more favorable than in the previous reports and was associated with seizure freedom. FCD1 is a frequent etiology for LOS and the cognitive outcome of patients with FCD1 seemed to be favorable.

Sturge-Weber syndrome presenting in late adulthood.

A 75-year-old woman presents to the acute medical take with confusion and headache following a road traffic accident. She had previously been fit and well, living alone with no assistance. Following multiple investigations, she was diagnosed with Sturge-Weber Syndrome, a rare neurocutaneous disorder that usually presents with seizures in childhood. This case highlights an unusual example of this syndrome, presenting for the first time later in life.

Sleep disorders and late-onset epilepsy of unknown origin: Understanding new trajectories to brain amyloidopathy.

The intertwining between epilepsy, sleep disorders and beta amyloid pathology has been progressively highlighted, as early identification and stratification of patients at high risk of cognitive decline is the need of the hour. Modification of the sleep-wake activity, such as sleep impairment or excessive daytime sleepiness, can critically affect cerebral beta amyloid levels. Both mice models and human studies have demonstrated a substantial increase in the burden of beta amyloid pathology after sleep-deprivation, with potential negative effects partially restored by sleep recovery. The accumulation of beta amyloid has been shown to be an early event in the course of Alzheimer's disease dementia. Beta amyloid accumulation has been linked to epileptic seizures epileptic seizures, with beta amyloid being itself pro-epileptogenic in mice models already at oligomeric stage, well before plaque deposition. Further supporting a potential relationship between beta amyloid and epilepsy: i) seizures happen in 1 out of oofut 10 patients with Alzheimer's disease in the prodromal stage, ii) epileptic activity accelerates cognitive decline in Alzheimer's disease, iii) people with late-onset epilepsy present a critically high risk of developing dementia. In this Review we highlight the role of beta amyloid as a potential shared mechanisms between sleep disorders, late-onset epilepsy, and cognitive decline.

A 48-Year-Old Woman With Chronic Cough, Dyspnea, and Bronchiectasis.

CASE PRESENTATION: A 48-year-old woman sought a second opinion for dyspnea and chronic productive cough; she was a never smoker. Mild respiratory symptoms persisted since childhood and had progressively worsened over the previous decade. In addition, an unintentional 30-pound weight loss had occurred over several years. Six years previously, a diagnosis of hypersensitivity pneumonitis was made following right upper lobe wedge resection that revealed chronic bronchiolitis with interstitial pneumonia and non-necrotizing granulomatous inflammation. Subsequent use of prednisone elicited mild intermittent improvement. She had used feather pillows in the past without any other significant exposures. There were no reports of sinus or GI symptoms.

Late-onset MADD: a rare cause of cirrhosis and acute liver failure?

Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a severe inborn error of fat metabolism. In late-onset MADD, hepatopathy in the form of steatosis is commonplace and considered a benign and stable condition that does not progress to more advanced stages of liver disease, however, progression to cirrhosis and acute liver failure (ALF) has been reported in two previous case reports. Here, we report a 22-year-old man, who suffered from late-onset MADD and died from cirrhosis and ALF. In the span of three months repeated clinical examinations, blood tests, and diagnostic imaging as well as liver biopsy revealed rapid progression of hepatopathy from steatosis to decompensated cirrhosis with portal hypertension. Routine studies for recognized etiologies found no evident cause besides MADD. This case report supports the findings of the two previous case reports and adds further evidence to the suggestion that late-onset MADD should be considered a rare cause of cirrhosis and ALF.