BACKGROUND: This study investigates primary lateral sclerosis (PLS) as a rare manifestation of the presenilin 1 (PSEN1) NM_000021 c.851C > T p.Pro284Leu variant in three siblings of a Colombian family, outlining its clinical and neuropathological features and their relationship to Alzheimer\'s disease (AD).
METHODS: Data were gathered using clinical evaluations, next-generation genetic sequencing, magnetic resonance imaging, biomarker analysis, and neuropathological examination.
RESULTS: Carriers of the PSEN1 Pro284Leu variant exhibited classic PLS symptoms, including unilateral onset and bulbar syndromes, along with cognitive decline. Neuropathology showed corticospinal tract degeneration without amyloid beta deposition in spinal white matter.
CONCLUSIONS: Our findings suggest an overlap between PLS and AD pathology in PSEN1 variant carriers. Results support considering PLS when diagnosing AD-related motor syndromes and including PSEN1 evaluation when performing genetic testing for PLS. The study highlights the need for further research to clarify the PLS-AD relationship, informing future treatments and clinical trials.
CONCLUSIONS: Pathogenic variants in presenilin 1 (PSEN1) can manifest as hereditary primary lateral sclerosis PSEN1 Pro284Leu carriers present motor, cognitive, and behavioral alterations  Cases had corticospinal tract microgliosis and severe Aβ pathology in motor cortex  There was no evidence of amyloid deposition in the spinal cord white matter  All the neuropathology images are available for online visualization  Myelin pallor in the spinal cord is confined to the lateral corticospinal tracts.

Spinal intramedullary epidermoids are rare intramedullary lesions of the spinal cord. They may be congenital or acquired with the congenital type often associated with spinal dysraphism and other spinal anomalies. The clinical presentation depends on the level of the involvement of the spinal cord. Management of these lesions is surgical excision. We report a case of intramedullary spinal epidermoid who presented with spastic paraparesis.

BACKGROUND: Hepatic myelopathy is a very rare neurological complication of chronic liver disease. Patients habitually present with progressive pure motor spastic paraparesis. This neurological dysfunction is almost always due to cirrhosis and portocaval shunt, either surgical or spontaneous.
METHODS: We report two cases of a 57-year-old man and a 37-year-old woman with progressive spastic paraparesis linked to cirrhosis and portal hypertension. The two patients are of Tunisian origin (north Africa). Magnetic resonance imaging of the spinal cord of two patients was normal, while brain magnetic resonance imaging showed a T2 hypersignals of the pallidums. These signs, in favor of hepatic encephalopathy in the two patients with cirrhosis with isolated progressive spastic paraparesis without bladder or sensory disorders, help to retain the diagnosis of hepatic myelopathy.
CONCLUSIONS: Hepatic myelopathy is a severe and debilitating neurological complication of chronic liver disease. The pathogenesis is misunderstood and seems to be multifactorial, including the selective neurotoxic role both of ammonia and other pathogenic neurotoxins. Usually a pathological brain magnetic resonance imaging showing a hepatic encephalopathy was documented, contrasting with a normal spinal cord magnetic resonance imaging that contributed to diagnosis of hepatic myelopathy. Conservative therapies such as ammonia-lowering measures, diet supplementation, antispastic drugs, and endovascular shunt occlusion show little benefit in improving disease symptoms. Liver transplantation performed at early stage can prevent disease progression and could probably allow for recovery.

Hepatic myelopathy (HM) is a rare neurological complication in the end stage of many liver diseases and is characterized by bilateral spastic paraparesis without sensory and sphincter dysfunction. It occurs owing to metabolic disorders and central nervous system dysfunction associated with cirrhosis. Without timely and effective clinical intervention, the prognosis of these patients is devastating. Although liver transplantation (LT) is an effective treatment for HM, the prognosis of these patients remains unsatisfactory. Early recognition and diagnosis of this disease are essential for improving patient prognosis. Here, we report a case of hepatitis B virus-associated decompensated cirrhosis with HM. The patient recovered well after LT. We also summarize the clinical characteristics and post-transplant outcomes of 25 patients with HM treated by LT through 2023, including this case.

METHODS: The rare association of Klinefelter syndrome and the clinical presentation of a late onset chronic progressive spastic paresis.
UNASSIGNED: An infertile, 61-year-old man, presented with late adult onset of gait problems, deep muscle pain, and bladder problems. He presented for the first time, years after onset with a spastic paraparesis with high arched feet. His parents had already died, but the patient described high arched feet with his mother. There is no further certain information about the parents. After thorough investigation, an additional X chromosome was found, whereafter the diagnosis of Klinefelter syndrome could be made. Other acquired and genetic causes for spastic paraparesis or hereditary motor neuropathy are excluded.
CONCLUSIONS: This rare case, together with three other literature reports by Sasaki (Intern Med 58(3):437-440, 2019), Sajra (Med Arh 61(1):52-53, 2007) and Matsubara et al., (J Neurol Neurosurg Psychiatry 57(5):640-642, 1994). suggests that Klinefelter syndrome can be associated with spastic paraparesis, besides the other various neuropsychiatric symptoms that are more commonly described.

UNASSIGNED: Chronic Idiopathic Spinal Cord Herniation (ISCH) is a very rare spinal cord deformation occurring predominantly in thoracic levels. ISCH lead to progressive myelopathy, spastic paraparesis and Brown Séquard syndrome.
UNASSIGNED: We want to hypothesize that a) the herniated segment can regain its function after untethering despite long-term and complete neurologic dysfunction. b) Intraoperative Electrophysiologic Monitoring (IOEPM) may identify intraoperative changes by monitoring specific neural pathways confirming the efficacy of the intervention in the forthcoming cases.
UNASSIGNED: It is a retrospective review of data of two cases prospectively collected showing improvement of neurological deficit in cases of ISCH in thoracic levels. We describe two patients with progressive neurological deficits due to ISCH who underwent surgery using electrophysiologic monitoring and have been followed to reach remarkable clinical improvement.
UNASSIGNED: The spastic paraparesis of the first case improved remarkably after surgery. Complete foot drop of the other case, persistent for 7 months before intervention, improved after the release of the herniated segment of the cord. Peroperative electrophysiological monitoring did not show changes during surgery.
UNASSIGNED: We want to hypothesize that the herniated segment can regain its function after untethering despite long-term and complete neurologic dysfunction. Intraoperative Electrophysiologic Monitoring (IOEPM) may confirm the efficacy of the intervention in the forthcoming cases.

A familial case of a rare autosomal dominant Alzheimer\'s disease (AD), related to PSEN1 gene (AD3, OMIM 607822), differing from common multifactorial form by earlier onset and, in part of cases, by accompanying neurological signs, spastic paraparesis particularly, is presented. The first sign in a female proband and in her son was paraparesis manifested at the age of 29 and 21 years, respectively. Cognitive disturbances developed soon; the former diagnosis was hereditary spastic paraplegia with cognitive impairment, In the proband examined in 2008 at 33 years old the diagnosis was not established. In the son examined in 2022 at 27 years old whole-exome sequencing detected a novel PSEN1 missense mutation p.Thr421Ala. The mutation was confirmed by Sanger sequencing in him, found out in the proband (who was severely disabled by that time) and excluded in her unaffected mother. Except for different age of onset, AD3 in two patients was similar, though in whole it is variable, also in relatives. The variability and rareness of the disease hampers clinical diagnostics. Massive parallel sequencing is a most reliable diagnostic method.
Описан семейный случай редкой аутосомно-доминантной болезни Альцгеймера, связанной с геном PSEN1 (БА3, OMIM 607822) и отличающейся от частой многофакторной формы значительно более ранним началом и в части случаев наличием неврологических симптомов, особенно прогрессирующего спастического парапареза. У женщины-пробанда и сына первым признаком был парапарез, манифестировавший в 29 лет и 21 год соответственно, быстро присоединились когнитивные расстройства; прежний диагноз: наследственная спастическая параплегия с когнитивными нарушениями. При обследовании больной в 33 года (2008 г.) диагноз не установили. У сына, обследованного в 27 лет (2022 г.), полноэкзомное секвенирование выявило новую миссенс-мутацию p.Thr421Ala в гене PSEN1; при верификации по Сэнгеру мутация подтверждена у него, найдена у пробанда, находившейся в состоянии глубокой психоневрологической инвалидизации, и исключена у ее здоровой матери. Кроме различия возраста начала, болезнь у пробанда и сына протекала сходно, но в целом БА3 разнообразна, в том числе внутрисемейно, что затрудняет клиническую диагностику. Высокопроизводительное экзомное секвенирование — надежный диагностический метод БА3 и сходных болезней.

UNASSIGNED: Hereditary spastic paraplegias (HSPs) are a group of inheritance diseases resulting in gait abnormalities, which may be detected using instrumented gait analysis. The aim of this systematic review was 2-fold: to identify specific gait analysis patterns and interventions improving gait in HSP subjects.
UNASSIGNED: A systematic review was conducted in PubMed, Cochrane Library, REHABDATA, and PEDro databases, in accordance with reporting guidelines of PRISMA statement and Cochrane\'s recommendation. The review protocol was recorded on the PROSPERO register. Patients with pure and complicated HSP of any age were included. All types of studies were included. Risk of bias, quality assessment, and meta-analysis were performed.
UNASSIGNED: Forty-two studies were included: 19 were related to gait analysis patterns, and 24 were intervention studies. The latter ones were limited to adults. HSP gait patterns were similar to cerebral palsy in younger subjects and stroke in adults. Knee hyperextension, reduced range of motion at knee, ankle, and hip, reduced foot lift, and increased rapid trunk and arm movements were reported. Botulinum injections reduced spasticity but uncovered weakness and improved gait velocity at follow-up. Weak evidence supported intrathecal baclofen, active intensive physical therapy (i.e., robot-assisted gait training, functional exercises, and hydrotherapy), and functional electrical stimulation. Some improvements but adverse events were reported after transcranial magnetic stimulation, transcutaneous spinal direct current stimulation, and spinal cord stimulation implant.
UNASSIGNED: Knee hyperextension, non-sagittal pelvic movements, and reduced ROM at the knee, ankle, and hip represent the most peculiar patterns in HSP, compared to diplegic cerebral palsy and stroke. Botulinum improved comfortable gait velocity after 2 months. Nonetheless, interventions reducing spasticity might result in ineffective functional outcomes unveiling weakness. Intensive active physical therapy and FES might improve gait velocity in the very short term.

BACKGROUND: Ethylmalonic encephalopathy (EE) is a rare intoxication-type metabolic disorder with multisystem involvement. It is caused by mutations in ETHE1, which encodes the ETHE1 enzyme in the mitochondrial matrix that plays a key role in hydrogen sulfide (H2S) detoxification acting as a sulphur dioxygenase.
RESULTS: This review focuses on the clinical, metabolic, genetic and neuroradiological features of 70 reported cases, including two new cases. The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively. A significant difference was found in EMA and C4 levels (p=0.003, p=0.0236) between classical and mild phenotypes. Urinary EMA, C4 and C5 levels were found to exhibit normal values in milder cases during attack-free periods. The most common ETHE1 gene homozygous state mutations were (p.R163Q) (c.488G>A), exon 4 deletion, (p.R163W)(c.487C>T), (p.Glu44ValfsTer62)(c.131_132delAG) and (p.M1I)(c.3G>T) mutations, respectively. Fifty-two patients underwent cranial MRI. Basal ganglia signal alterations were detected in 42 cases. Of the 70 cases, eight had a mild phenotype and slow neurological progression with low levels of ethylmalonic acid (EMA) and C4 acylcarnitine. The current age of alive patients in the published articles with mild phenotype was significantly higher than the classical phenotype. (p=0.002). Reducing the accumulation and inducing detoxification of sulfide is the main long-term treatment strategy for EE, including metronidazole, N-acetylcysteine (NAC), dietary modification, liver transplantation and continuous renal replacement therapy (CRRT).
CONCLUSIONS: Measuring EMA and C4 acylcarnitine during metabolic attacks is critical to diagnosing EE, allowing for early treatment initiation to prevent further encephalopathic crises. Experience with liver transplantation, diet and CRRT, is currently limited. An early multidisciplinary approach with combination therapies is vital to prevent irreversible neurological damage.

Leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with white matter abnormalities detected on magnetic resonance imaging (MRI) often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia, and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation; one of the causes is hyperhomocystinemia due to 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency. MTHFR deficiency is a genetic disorder that can occur at any age and can be easily detected by increased serum homocysteine levels and it is a treatable cause. Metabolic therapies like betaine were shown to be effective in children and adults to stop the disease progression and sometimes improve neurologic disabilities. Herein, we report a 16-year-old male with gradually progressive spastic paraparesis with history of cerebral venous sinus thrombosis and poor scholastic performance. The patient was diagnosed with MTHFR enzyme deficiency presenting as leukodystrophy with spastic paraparesis, which is treatable on early diagnosis. Treatment with betaine produced a rapid decline of homocysteine and improved the condition.