Ingrid Faber

Clinical features and management of hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions.

Non-motor symptoms in patients with hereditary spastic paraplegia caused by SPG4 mutations.

Non‐motor manifestations are frequently overlooked in degenerative disorders and little is known about their frequency and clinical relevance in SPG4 hereditary spastic paraplegia (SPG4‐HSP).

Autoimmune neuropathies associated to rheumatic diseases

Systemic manifestations are frequent in autoimmune rheumatic diseases and include peripheral nervous system damage. Neuron cell body, axons and myelin sheath may all be affected in this context. This involvement results in severe and sometimes disabling symptoms. Sensory, motor and autonomic features may be present in different patterns that emerge as peculiar clinical pictures. Prompt recognition of these neuropathies is pivotal to guide treatment and reduce the risks of long term disability. In this review, we aim to describe the main immune-mediated neuropathies associated to rheumatic diseases: sensory neuronopathies, multiple mononeuropathies and chronic inflammatory demyelinating polyradiculoneuropathy, with an emphasis on clinical features and therapeutic options.

A new phenotype associated with homozygous GRN mutations: complicated spastic paraplegia.

Sirs, GRN heterozygous mutations are among the most common causes of autosomal dominant frontotemporal lobar degeneration (FTLD) [1]. In 2012, Smith et al. [2] described homozygous GRN mutations causing a novel type of progressive myoclonus epilepsy ceroid neuronal lipofuscinosis type 11 (CLN11). The key initial manifestations were early adulthood visual loss and generalized epilepsy. We report a patient with homozygous GRN mutations who had spastic paraplegia (SPG) as the first manifestation of disease. A 25-year-old female came for evaluation with a 4-year history of progressive gait impairment and urinary incontinence. Over the last year she had developed mood lability and delusional thoughts. Recently she had been experiencing photosensitive seizures which were preceded by visual aura. She had low scholar performance since early childhood. Consanguinity was suspected since her parents came from the same small village. Parents and brother were all reported to be healthy but unfortunately were unavailable for evaluation. During interview, family members reported that the proband’s father and mother are now in their 50s and deny significant cognitive or behavioral complaints (Fig. 1a). Neurological examination revealed high arched feet, appendicular ataxia, lower limb spasticity, widespread hyperreflexia and upgoing toes. Her gait was spastic, but she also presented widened base indicating concomitant axial ataxia. Magnetic resonance imaging revealed global and severe cerebellar atrophy (Fig. 1b). Serial electroencephalograms revealed a slow wave background activity and epileptiform discharges predominating in posterior regions during photostimulation. Epilepsy was controlled with lamotrigine 400 mg and no myoclonus was ever documented. During the following 2 years gait disturbance progressed and walking was only possible with bilateral support. Her husband mentioned inattention, word-finding difficulty as well as poor task completion and decision making. Frequent crying, suicidal thoughts and aggressive behavior were also evident during consultation. A MOCA test revealed severe cognitive impairment (3/30 points); only time orientation tasks were correctly answered. Ophthalmological investigation was not feasible due to poor cooperation. Considering a diagnosis of complicated SPG and due to the genetic heterogeneity of this group of disorders, we proceeded to wholeexome sequencing performed at the Illumina Hiseq 2500 platform. Variants not present at single-nucleotide polymorphism databases and fitting a recessive model were prioritized for further analysis. A homozygous c.767_768insCC mutation was identified at the GRN gene (Fig. 1c). This new variant is predicted to be pathogenic by in silico analysis (http://www.mutationtaster.org/). It disrupts the open reading frame and leads to premature termination of the transcript. This case highlights the pleiotropic effects of progranulin deficiency according to each specific genotype. Heterozygous individuals present with late-onset cognitive and behavioral deficits. In a homozygous state, an almost complete absence of progranulin results in a pleomorphic clinical picture (with predominant visual loss and/or epilepsy) beginning in the early 20s [3,4]. Progranulin plays a key role in neuronal survival and different neuronal populations present different vulnerabilities according to the degree of haploinsufficiency. Additionally, significant ethical challenges emerge from the diagnosis of an autosomal recessive disease in a scenario where more than one mode of inheritance is possible. Taking into account the high penetrance of GRN mutations (up to 97.3%), the patient’s first-degree relatives have a high likelihood of developing FTLD [5]. We acknowledge that the phenotypic spectrum associated with homozygous GRN mutations is wide and cerebellar ataxia is often a major finding. Despite that, the unique feature of our case is the gait disorder heralding disease onset. She indeed presented with a mixed gait disturbance (spasticity and ataxia) but spasticity certainly dominated the clinical picture. Homozygous GRN mutations may cause a spastic ataxia phenotype. This gene should be included in the differential diagnosis of complicated SPGs and ataxias, particularly when epilepsy or visual loss is present.

SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage

SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.

Structural signature of classical versus late-onset friedreich's ataxia by Multimodality brain MRI

Friedreichs ataxia (FRDA) is the most common autosomal‐recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities, and slowly progressive ataxia. However, some individuals manifest the disease after the age of 25 years and are classified as late‐onset FRDA (LOFA). Therefore, we propose a transversal multimodal MRI‐based study to investigate which anatomical substrates are involved in classical (cFRDA) and LOFA.

Cognitive dysfunction in hereditary spastic paraplegias and other motor neuron disorders

Hereditary spastic paraplegia (HSP) is a diverse group of single-gene disorders that share the predominant clinical feature of progressive lower limb spasticity and weakness. More than 70 different genetic subtypes have been described and all modes of inheritance are possible. Intellectual dysfunction in HSP is frequent in recessive forms but rare in dominant families. It may manifest by either mental retardation and/or cognitive decline. The latter may be subtle, restricted to executive dysfunction or may evolve to severe dementia. The cognitive profile is thought to depend largely on the genetic subtype of HSP, although wide phenotypic variability within the same genetic subtype and also within the same family can be found.

Translation and validation into Brazilian Portuguese of the Spastic Paraplegia Rating Scale (SPRS)

OBJECTIVE To translate and validate the Spastic Paraplegia Rating Scale (SPRS) into Brazilian-Portuguese. METHOD Two experienced and English-fluent neurologists translated SPRS into Portuguese, creating SPRS-BR. We then assessed inter and intra-rater reliability of this version using coefficients of correlation and variability in a cohort of 30 patients. RESULTS Mean age of patients and disease duration were 47.7 ± 10.5 and 17.0 ± 10.6 years, respectively. Twenty-one had pure HSP and SPG4 was the most frequent genotype. Mean Rankin and SPRS-BR scores were 2.2 ± 0.9 and 19.9 ± 9.9, respectively. Mean intra and inter-rater correlation coefficients of SPRS-BR scores were 0.951 and 0.934, whereas coefficients of variation were 11.5% (inter-rater) and 9.9% (intra-rater). Cronbachs alpha for the whole SPRS-BR scale was 0.873. CONCLUSION SPRS-BR is a useful, reliable and valid clinical instrument.

SPG11-related parkinsonism: Clinical profile, molecular imaging and l-dopa response: SPG11-Related Parkinsonism

Background: Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias.

Developmental and Neurodegenerative Damage in Friedreich Ataxia

Friedreichs ataxia (FRDA) is the most common autosomal‐recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities and slowly progressive ataxia. All magnetic resonance imaging (MRI)‐based studies have focused on the evaluation of adult patients. Therefore, we designed a cross‐sectional multimodal MRI‐based study to investigate the anatomical substrates involved in the early stages of FRDA.