Consensus recommendations for the classification and long-term follow up of infants who screen positive for Krabbe Disease.

OBJECTIVE: To provide updated evidence and consensus-based recommendations for the classification of individuals who screen positive for Krabbe Disease (KD) and recommendations for long-term follow-up for those who are at risk for late onset Krabbe Disease (LOKD). METHODS: KD experts (KD NBS Council) met between July 2017 and June 2020 to develop consensus-based classification and follow-up recommendations. The resulting newly proposed recommendations were assessed in a historical cohort of 47 newborns from New York State who were originally classified at moderate or high risk for LOKD. RESULTS: Infants identified by newborn screening with possible KD should enter one of three clinical follow-up pathways (Early infantile KD, at-risk for LOKD, or unaffected), based on galactocerebrosidase (GALC) activity, psychosine concentration, and GALC genotype. Patients considered at-risk for LOKD based on low GALC activity and an intermediate psychosine concentration are further split into a high-risk or low-risk follow-up pathway based on genotype. Review of the historical New York State cohort found that the updated follow-up recommendations would reduce follow up testing by 88%. CONCLUSION: The KD NBS Council has presented updated consensus recommendations for efficient and effective classification and follow-up of NBS positive patients with a focus on long-term follow-up of those at-risk for LOKD.

Biochemical, cell biological, pathological, and therapeutic aspects of Krabbe's disease.

Krabbe's disease (KD; also called globoid cell leukodystrophy) is a genetic disorder involving demyelination of the central (CNS) and peripheral (PNS) nervous systems. The disease may be subdivided into three types, an infantile form, which is the most common and severe; a juvenile form; and a rare adult form. KD is an autosomal recessive disorder caused by a deficiency of galactocerebrosidase activity in lysosomes, leading to accumulation of galactoceramide and neurotoxic galactosylsphingosine (psychosine [PSY]) in macrophages (globoid cells) as well as neural cells, especially in oligodendrocytes and Schwann cells. This ultimately results in damage to myelin in both CNS and PNS with associated morbidity and mortality. Accumulation of PSY, a lysolipid with detergent-like properties, over a threshold level could trigger membrane destabilization, leading to cell lysis. Moreover, subthreshold concentrations of PSY trigger cell signaling pathways that induce oxidative stress, mitochondrial dysfunction, apoptosis, inflammation, endothelial/vascular dysfunctions, and neuronal and axonal damage. From the time the "psychosine hypothesis" was proposed, considerable efforts have been made in search of an effective therapy for lowering PSY load with pharmacological, gene, and stem cell approaches to attenuate PSY-induced neurotoxicity. This Review focuses on the recent advances and prospective research for understanding disease mechanisms and therapeutic approaches for KD. © 2016 Wiley Periodicals, Inc.

A staging system for infantile Krabbe disease to predict outcome after unrelated umbilical cord blood transplantation.

OBJECTIVE: Infantile Krabbe disease, a rare neurodegenerative disorder that leads to rapid demyelination, dysmyelination, and death in the first 2 years of life, is responsive to treatment with umbilical cord blood transplantation provided that the patient is treated in the first weeks of life. At present, family history is the only way to identify patients that are asymptomatic with most patients being diagnosed after onset of symptoms. We hypothesized that a staging system based on clinical indicators and neurophysiological and neuroimaging measures can predict posttreatment variation in patients diagnosed with infantile Krabbe disease. METHODS: A retrospective review of pretransplant clinical indicators and neurodevelopmental, brain imaging and neurophysiological measures was performed in 42 patients being considered for treatment with umbilical cord blood transplantation. Based on these evaluations, an expert system approach was used to develop a staging system for infantile Krabbe disease. Another set of analyses in the subset of patients who were transplanted (n = 29) evaluated the association between pretransplant stage of disease and posttransplant neurodevelopmental outcomes. RESULTS: A staging algorithm for infants with infantile Krabbe disease was developed and tested for predicting neurodevelopmental outcome after umbilical cord blood transplantation. Standard neurophysiological and neuroimaging tests were not useful in the staging algorithm. Clinical indicators were found to best classify stage of disease. Pretransplant stage was found to be predictive of neurodevelopmental outcome. CONCLUSIONS: We conclude that the clinical staging system based solely on signs and symptoms of disease can be used to predict outcomes after umbilical cord blood transplantation. This staging system can be used prospectively to guide physicians unfamiliar with the disorder in evaluating, monitoring, and counseling families about treatment outcomes. The staging will be useful for both patients diagnosed with infantile Krabbe disease because of clinical symptoms and those identified through neonatal screening programs.

Krabbe disease: neurophysiologic studies and MRI correlations.

BACKGROUND: Krabbe disease (KD) is a rare hereditary leukodystrophy affecting children mostly in the first 6 months of life; later onset has been reported as well. OBJECTIVE: To review abnormalities in neurophysiologic studies in children with KD and determine if there is a correlation between these studies and disease severity as measured by MRI scans. METHODS: KD patients with at least one neurophysiologic study and one MRI scan at the authors' institution were reviewed. Relationships between KD type, neurophysiologic studies, and severity of disease as measured by MRI were explored. RESULTS: Data were available for 26 children: 20 with early infantile KD (EIKD) and 6 with late-onset KD (LOKD). Flash visual evoked potentials were abnormal in 53% of EIKD children, whereas none of the LOKD children had an abnormal study. Brainstem auditory evoked potentials were abnormal in 88% of EIKD and 40% of LOKD children. EEGs were abnormal in 65% of EIKD and 33% of LOKD children. Nerve conduction studies were abnormal in all children with EIKD and in 20% of LOKD children. Abnormal neurophysiologic studies correlated with more extensive disease as measured by MRI scans. CONCLUSIONS: Children with early infantile Krabbe disease and late-onset Krabbe disease have different patterns of abnormalities in neurophysiologic studies. These studies offer an objective means of assessing KD and correlate well with disease severity measured by MRI scans.

Clinical and neuroradiological findings in classic infantile and late-onset globoid-cell leukodystrophy (Krabbe disease).

In the present study the clinical course and imaging of early and late-onset forms of Krabbe disease are analyzed. We report on 11 patients with a biochemical diagnosis of galactosyl ceramide beta-galactoside deficiency. Two presented as the classic infantile form and died within the second year of life. In 9 children the first clinical signs, such as gait difficulties and visual failure, started after age 2 years. All these patients developed slow regression of motor and mental capacities, and most of them died within their first decade. In patients of both groups computed tomography (CT) and magnetic resonance imaging (MRI) were performed. In the late-onset form, hypodensities of the central white matter and pyramidal tracts were the leading radiological signs, whereas in the early-onset form, hyperdensities and cerebellar white matter lesions were also detected. From our results it becomes clear that variability of Krabbe disease refers not only to clinical manifestation but also to CT and MRI findings. Better knowledge of phenotypic and radiological diversity will help to understand the pathogenesis of the disease.

Demyelinating hereditary neuropathies in children: a morphometric and ultrastructural study.

Twenty-three cases of hereditary demyelinating neuropathies are reported, 13 with different types of hereditary motor and sensory neuropathy (HMSN) and 9 with globoid cell or meta-chromatic leucodystrophies. Ultrastructural and morpho-metric studies showed some critical pathological features emphasizing: 1) the variability of the recessive forms of HMSN; 2) the morphological distinction between HMSN type I and type III; and 3) differences between these types of HMSN and other "onion bulb" neuropathies such as those found in leucodystrophies, which account for distinct underlying mechanisms.

Nosology of the leukodystrophies: ultrastructural contributions.

Ultrastructural aspects of some of the conditions usually included as "leukodystrophies" are described. In metachromatic leukodystrophy, the most striking ultrastructural features include a variety of inclusions within cells some of which can be identified as oligodendroglia. Some inclusions were relatively amorphous while others possess a well-defined lamellar pattern. The fine structure of the globoid-epithelioid cells of Krabbe's disease differs from that of the usual macrophage and contains membrane-bound areas of relative translucency as well as abundant amorphous moderately osmiophiclic deposits. Epithelioid cells are seen in the perivascular spaces which favors their origin from mesodermal elements and is against their being derived from macroglia. In sudanophilic leukodystrophy there are macrophages which are not distinguishable from macrophages seen in areas of myelin destruction from whatever cause. In the spongy degeneration of infants, there is a peculiar myelin abnormality with splitting of the intraperiod line of the myelin lamellae and the existance of large abnormal mitochondria in astrocyte cytoplasm. There may also be vaculolization of significance within oliogodendroglia cytoplasm. The Rosenthal fibers seen in Alexander's type of leukodystrophy appear as osmiophilic masses in astroyte cytoplasm and probably consist of altered glial filaments.