RARE DISEASE
Hypomyelination with atrophy of basal ganglia and cerebellum
Hypomyelination with atrophy of basal ganglia and cerebellum
Hypomyelination with atrophy of basal ganglia and cerebellum
Synonyms: H-ABC
Synonyms: H-ABC
Synonyms: H-ABC
Drug discovery
1
drug
With orphan designation
Overview
Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC) is a rare TUBB4A-linked leukodystrophy characterized by progressive hypomyelination, putaminal atrophy, and cerebellar degeneration. Clinical features include extrapyramidal movement disorders (dystonia, choreoathetosis), spasticity, ataxia, and variable cognitive impairment. Diagnosis relies on distinctive MRI patterns (hypomyelination, basal ganglia/cerebellar atrophy) and confirmed TUBB4A mutations. Prognosis is variable, with no curative therapies available [1][3][14].
Burden
Progressive motor decline, leading to loss of ambulation (60% by age 10) [14][16].
High care needs: 80% require wheelchair assistance, 40% develop life-threatening dysphagia/respiratory complications [12][18].
Mortality: 30% die in childhood; survivors often face severe disability, with the oldest reported patient aged 29 [4][14].
Therapies
Symptomatic management: Levodopa/carbidopa for dystonia [8], intrathecal baclofen pumps, and botulinum toxin for spasticity [20].
Supportive care: Physical therapy, dysphagia management, and seizure control [3][12].
Experimental approaches: TUBB4A-targeted gene therapy (AAV-mediated) and antisense oligonucleotides (ASOs) in preclinical trials [3][13].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
11 drug discovery papers about Hypomyelination with atrophy of basal ganglia and cerebellum, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
11 drug discovery papers about Hypomyelination with atrophy of basal ganglia and cerebellum, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-03-01 | 4-aminopyridine improves evoked potentials and ambulation in the taiep rat: A model of hypomyelination with atrophy of basal ganglia and cerebellum
The taiep rat is a tubulin mutant with an early hypomyelination followed by progressive demyelination of the central nervous system due to a point mutation in the Tubb4a gene. It shows clinical, radiological, and pathological signs like those of the human leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Taiep rats had tremor, ataxia, immobility episodes, epilepsy, and paralysis; the acronym of these signs given the name to this autosomal recessive trait. The aim of this study was to analyze the characteristics of somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) in adult taiep rats and in a patient suffering from H-ABC. Additionally, we evaluated the effects of 4-aminopyridine (4-AP) on sensory responses and locomotion and finally, we compared myelin loss in the spinal cord of adult taiep and wild type (WT) rats using immunostaining. Our results showed delayed SSEPs in the upper and the absence of them in the lower extremities in a human patient. In taiep rats SSEPs had a delayed second negative evoked responses and were more susceptible to delayed responses with iterative stimulation with respect to WT. MEPs were produced by bipolar stimulation of the primary motor cortex generating a direct wave in WT rats followed by several indirect waves, but taiep rats had fused MEPs. Importantly, taiep SSEPs improved after systemic administration of 4-AP, a potassium channel blocker, and this drug induced an increase in the horizontal displacement measured in a novelty-induced locomotor test. In taiep subjects have a significant decrease in the immunostaining of myelin in the anterior and ventral funiculi of the lumbar spinal cord with respect to WT rats. In conclusion, evoked potentials are useful to evaluate myelin alterations in a leukodystrophy, which improved after systemic administration of 4-AP. Our results have a translational value because our findings have implications in future medical trials for H-ABC patients or with other leukodystrophies.
2022-01-13 | Long-term taurine administration improves motor skills in a tubulinopathy rat model by decreasing oxidative stress and promoting myelination.
The taiep rat undergoes hypomyelination and progressive demyelination caused by an abnormal microtubule accumulation in oligodendrocytes, which elicits neuroinflammation and motor behavior dysfunction. Based on taurine antioxidant and proliferative actions, this work explored whether its sustained administration from the embryonic age to adulthood could prevent neuroinflammation, stimulate cell proliferation, promote myelination, and relieve motor impairment. Taurine (50 mg/L of drinking water = 50 ppm) was given to taiep pregnant rats on gestational day 15 and afterward to the male offspring until eight months of age. We measured the levels of nitric oxide (NO), malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA), CXCL1, CXCR2 receptor, growth factors (BNDF and FGF2), cell proliferation, and myelin content over time. Integral motor behavior was also evaluated. Our results showed that taurine administration significantly decreased NO and MDA + 4-HDA levels, increased cell proliferation, and promoted myelination in an age- and brain region-dependent fashion compared with untreated taiep rats. Taurine effect on chemokines and growth factors was also variable. Taurine improved vestibular reflexes and limb muscular strength in perinatal rats and fine movements and immobility episodes in adult rats. These results show that chronic taurine administration partially alleviates the taiep neuropathology.
2017-08-29 | TUBB4A mutations result in specific neuronal and oligodendrocytic defects that closely match clinically distinct phenotypes
Abstract Hypomyelinating leukodystrophies are heritable disorders defined by lack of development of brain myelin, but the cellular mechanisms of hypomyelination are often poorly understood. Mutations in TUBB4A, encoding the tubulin isoform tubulin beta class IVA (Tubb4a), result in the symptom complex of hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC). Additionally, TUBB4A mutations are known to result in a broad phenotypic spectrum, ranging from primary dystonia (DYT4), isolated hypomyelination with spastic quadriplegia, and an infantile onset encephalopathy, suggesting multiple cell types may be involved. We present a study of the cellular effects of TUBB4A mutations responsible for H-ABC (p.Asp249Asn), DYT4 (p.Arg2Gly), a severe combined phenotype with hypomyelination and encephalopathy (p.Asn414Lys), as well as milder phenotypes causing isolated hypomyelination (p.Val255Ile and p.Arg282Pro). We used a combination of histopathological, biochemical and cellular approaches to determine how these different mutations may have variable cellular effects in neurons and/or oligodendrocytes. Our results demonstrate that specific mutations lead to either purely neuronal, combined neuronal and oligodendrocytic or purely oligodendrocytic defects that closely match their respective clinical phenotypes. Thus, the DYT4 mutation that leads to phenotypes attributable to neuronal dysfunction results in altered neuronal morphology, but with unchanged tubulin quantity and polymerization, with normal oligodendrocyte morphology and myelin gene expression. Conversely, mutations associated with isolated hypomyelination (p.Val255Ile and p.Arg282Pro) and the severe combined phenotype (p.Asn414Lys) resulted in normal neuronal morphology but were associated with altered oligodendrocyte morphology, myelin gene expression, and microtubule dysfunction. The H-ABC mutation (p.Asp249Asn) that exhibits a combined neuronal and myelin phenotype had overlapping cellular defects involving both neuronal and oligodendrocyte cell types in vitro. Only mutations causing hypomyelination phenotypes showed altered microtubule dynamics and acted through a dominant toxic gain of function mechanism. The DYT4 mutation had no impact on microtubule dynamics suggesting a distinct mechanism of action. In summary, the different clinical phenotypes associated with TUBB4A reflect the selective and specific cellular effects of the causative mutations. Cellular specificity of disease pathogenesis is relevant to developing targeted treatments for this disabling condition.
2016-03-01 | TUBB4A-related hypomyelinating leukodystrophy: New insights from a series of 12 patients
Background Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) was first described in 2002. After the recent identification of TUBB4A mutation as the genetic basis of the disease, the clinical and neuroimaging phenotype related to TUBB4A mutations expanded, ranging from primary dystonia type 4 with normal MRI to severe H-ABC cases. Patients and methods The study included patients referred to us for an unclassified hypomyelinating leukodystrophy. We selected patients with deleterious heterozygous TUBB4A mutations. Molecular analysis of TUBB4A was performed on genomic DNA extracted from peripheral blood. Results The series included 12 patients (5 females and 7 males). Five patients carried the common mutation c.745G > A (p.Asp249Asn), while the remaining harbored different mutations. Three new mutations were found in 5 patients. Clinical and neuroimaging observations are described. A clear correlation between the clinical presentation and the genotype seems to be absent in our group of 12 patients. Conclusions TUBB4A-mutated patients manifest a comparable clinical and neuroimaging picture but they can differ from each other in terms of rate of disease progression. Extrapyramidal signs can be absent in the first stages of the disease, and a careful evaluation of MRI is fundamental to obtain the final diagnosis. From a therapeutic perspective a trial with l-dopa should be considered in all patients presenting extrapyramidal symptoms.
2006-06-29 | Effective treatment with levodopa and carbidopa for hypomyelination with atrophy of the basal ganglia and cerebellum.
Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare leukoencephalopathy presenting in the infantile period and characterized by diffuse cerebral hypomyelination, and atrophy of the basal ganglia and cerebellum. As patients with H-ABC lack remarkable laboratory findings, the diagnosis is based on brain magnetic resonance imaging findings alone. Only eight cases have been reported in the literature, and thus the natural course and treatment of this disease are not fully understood. We report a 35-month-old boy with H-ABC who had hemidystonia, hypomyelination, and cerebellar ataxia. We diagnosed H-ABC after considering a thorough differential diagnosis, excluding other diseases involving hemidystonia, hypomyelination, and cerebellar ataxia. Furthermore, technetium-99m ethyl cysteinate dimmer-single-photon emission computerized tomography (Tc-ECD-SPECT) and positron emission tomography with fluorodeoxyglucose (18)F (FDG-PET) revealed decreased blood flow and glucose metabolism in the bilateral lenticular nucleus, thalamus, and cerebellum. A peroral levodopa preparation containing carbidopa (levodopa-carbidopa) was effective at ameliorating and stopping the progression of the patient's dystonia (final effective doses: levodopa, 200 mg/day and carbidopa, 20 mg/day). This is the first case report of a Japanese patient with H-ABC and treatment for this disease. Levodopa-carbidopa may be an effective treatment for H-ABC.
oligonucleotides
2026-08-06 | Deletion of TUBB4A mitigates the oligodendrocyte and neuronal deficits in human iPSCs derived from individuals affected by H-ABC
Abstract TUBB4A -related leukodystrophy ( TUBB4A -LD) is a rare neurologic disorder with a broad spectrum of phenotypes, including severe early infantile encephalopathy, late infantile Hypomyelination with Atrophy of the Basal ganglia and Cerebellum (H-ABC), and milder late infantile forms. H-ABC is closely associated with a recurrent pathogenic variant, p.Asp249Asn, in the gene encoding tubulin beta class IVA (TUBB4A), a microtubule component. H-ABC presents with progressive dystonia, mobility loss, aphasia, and swallowing dysfunction in childhood. H-ABC results in cell-autonomous deficits in oligodendrocytes (OLs), cerebellar granule neurons, and medium spiny neurons (MSNs). Antisense oligonucleotides targeting Tubb4a can alleviate symptoms in H-ABC mouse models. However, the efficacy and safety of TUBB4A knockout in human cells remain poorly understood. We studied patient-derived TUBB4A D249N , TUBB4A KO , and control individual pluripotent stem cells (iPSCs). TUBB4A D249N iPSC-derived OLs failed to mature, showing less complexity and myelination, reduced microtubule acetylation and detyrosination. TUBB4A D249N iPSC-derived MSNs also showed impaired maturation and neurite extension. TUBB4A KO in mutant iPSCs reduced cellular deficits and was well tolerated. These findings support that suppression of TUBB4A could be a safe, effective therapy for TUBB4A - LD .
2024-08-27 | Therapeutic suppression of Tubb4a rescues H-ABC leukodystrophy
Abstract Hypomyelination and atrophy of basal ganglia and cerebellum (H-ABC) is a rare leukodystrophy associated with causal variants in β-tubulin 4A ( TUBB4A ). The recurring variant p.Asp249Asn (D249N) presents in infancy with dystonia, communication deficits, and loss of ambulation during the first decade of life. In this study, we characterized a genetic murine series ( Tubb4a KO/KO , Tubb4a D249N/+ , Tubb4a D249N/KO, and Tubb4a D249N/D249N ) to demonstrate that disease severity correlates with the expression of mutant Tubb4a and relative preservation of WT tubulin. To further evaluate the translational potential of Tubb4a suppression as a therapy in H-ABC, we identified a well-tolerated Tubb4a -targeted antisense oligonucleotide (ASO) candidate that selectively reduces Tubb4a in vitro and in vivo . Notably, single intracerebroventricular (i.c.v.) administration of ASO in postnatal Tubb4a D249N/KO mice drastically extends its lifespan, improves motor phenotypes, and reduces seizures. Neuropathologically, ASO treatment in Tubb4a D249N/KO mice restores myelin and oligodendrocyte survival. Furthermore, in vivo visual evoked potential latencies recover in ASO-treated Tubb4a D249N/KO mice. This is the first preclinical proof-of-concept for Tubb4a suppression via ASO as a disease-modifying therapy for H-ABC.
proteins
2025-10-19 | Exacerbation of absence seizures by central prolactin in female taiep rats: An animal model of epilepsy-prone leukodystrophy.
Absence seizures are a type of generalized epilepsy characterized by spike-wave discharges (SWDs) in the electroencephalogram (EEG). This condition affects girls more frequently than boys and has a worse prognosis in women during puberty and adulthood. These characteristics of sexual dimorphism and age predominance could be attributed to changes in plasma hormone levels during development, particularly during puberty, which can modulate the cortico-thalamic circuit responsible for generating and sustaining SWDs. Prolactin is a peptide hormone secreted by adenohypophysis, exhibits sexual dimorphism and undergoes an increase during puberty. In this study, we employed female taiep rats, a well-validated animal model of leukodystrophy known as hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). This model has a sexually dimorphic pattern of SWDs, with males exhibiting greater susceptibility to the condition. The rats were ovariectomized and electrodes were implanted for EEGs and a stainless-steel cannula for administration of rat prolactin via intracerebroventricular (i.c.v.) injection. Five 12-hour EEGs were performed with fixed 48-hour start intervals: the control EEG followed by i.c.v. prolactin administration at doses of 0.5, 1, 2, or 4 μg/2 μL. The frequency of SWDs increased significantly with the 2 and 4 μg/2 μL doses of prolactin. The mean duration of SWDs increased significantly with all doses evaluated, with the greatest effect observed 6 h after 4 μg/2 μL of prolactin, which doubled the mean duration obtained in control conditions. Additionally, prolactin 4 μg/2 μL significantly decreased the latency to the first SWDs. We propose that prolactin is capable of neuromodulating the thalamo-cortical circuit responsible for spike-wave discharges.
small molecules
2024-03-01 | 4-aminopyridine improves evoked potentials and ambulation in the taiep rat: A model of hypomyelination with atrophy of basal ganglia and cerebellum
The taiep rat is a tubulin mutant with an early hypomyelination followed by progressive demyelination of the central nervous system due to a point mutation in the Tubb4a gene. It shows clinical, radiological, and pathological signs like those of the human leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Taiep rats had tremor, ataxia, immobility episodes, epilepsy, and paralysis; the acronym of these signs given the name to this autosomal recessive trait. The aim of this study was to analyze the characteristics of somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) in adult taiep rats and in a patient suffering from H-ABC. Additionally, we evaluated the effects of 4-aminopyridine (4-AP) on sensory responses and locomotion and finally, we compared myelin loss in the spinal cord of adult taiep and wild type (WT) rats using immunostaining. Our results showed delayed SSEPs in the upper and the absence of them in the lower extremities in a human patient. In taiep rats SSEPs had a delayed second negative evoked responses and were more susceptible to delayed responses with iterative stimulation with respect to WT. MEPs were produced by bipolar stimulation of the primary motor cortex generating a direct wave in WT rats followed by several indirect waves, but taiep rats had fused MEPs. Importantly, taiep SSEPs improved after systemic administration of 4-AP, a potassium channel blocker, and this drug induced an increase in the horizontal displacement measured in a novelty-induced locomotor test. In taiep subjects have a significant decrease in the immunostaining of myelin in the anterior and ventral funiculi of the lumbar spinal cord with respect to WT rats. In conclusion, evoked potentials are useful to evaluate myelin alterations in a leukodystrophy, which improved after systemic administration of 4-AP. Our results have a translational value because our findings have implications in future medical trials for H-ABC patients or with other leukodystrophies.
2022-01-13 | Long-term taurine administration improves motor skills in a tubulinopathy rat model by decreasing oxidative stress and promoting myelination.
The taiep rat undergoes hypomyelination and progressive demyelination caused by an abnormal microtubule accumulation in oligodendrocytes, which elicits neuroinflammation and motor behavior dysfunction. Based on taurine antioxidant and proliferative actions, this work explored whether its sustained administration from the embryonic age to adulthood could prevent neuroinflammation, stimulate cell proliferation, promote myelination, and relieve motor impairment. Taurine (50 mg/L of drinking water = 50 ppm) was given to taiep pregnant rats on gestational day 15 and afterward to the male offspring until eight months of age. We measured the levels of nitric oxide (NO), malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA), CXCL1, CXCR2 receptor, growth factors (BNDF and FGF2), cell proliferation, and myelin content over time. Integral motor behavior was also evaluated. Our results showed that taurine administration significantly decreased NO and MDA + 4-HDA levels, increased cell proliferation, and promoted myelination in an age- and brain region-dependent fashion compared with untreated taiep rats. Taurine effect on chemokines and growth factors was also variable. Taurine improved vestibular reflexes and limb muscular strength in perinatal rats and fine movements and immobility episodes in adult rats. These results show that chronic taurine administration partially alleviates the taiep neuropathology.
2017-08-29 | TUBB4A mutations result in specific neuronal and oligodendrocytic defects that closely match clinically distinct phenotypes
Abstract Hypomyelinating leukodystrophies are heritable disorders defined by lack of development of brain myelin, but the cellular mechanisms of hypomyelination are often poorly understood. Mutations in TUBB4A, encoding the tubulin isoform tubulin beta class IVA (Tubb4a), result in the symptom complex of hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC). Additionally, TUBB4A mutations are known to result in a broad phenotypic spectrum, ranging from primary dystonia (DYT4), isolated hypomyelination with spastic quadriplegia, and an infantile onset encephalopathy, suggesting multiple cell types may be involved. We present a study of the cellular effects of TUBB4A mutations responsible for H-ABC (p.Asp249Asn), DYT4 (p.Arg2Gly), a severe combined phenotype with hypomyelination and encephalopathy (p.Asn414Lys), as well as milder phenotypes causing isolated hypomyelination (p.Val255Ile and p.Arg282Pro). We used a combination of histopathological, biochemical and cellular approaches to determine how these different mutations may have variable cellular effects in neurons and/or oligodendrocytes. Our results demonstrate that specific mutations lead to either purely neuronal, combined neuronal and oligodendrocytic or purely oligodendrocytic defects that closely match their respective clinical phenotypes. Thus, the DYT4 mutation that leads to phenotypes attributable to neuronal dysfunction results in altered neuronal morphology, but with unchanged tubulin quantity and polymerization, with normal oligodendrocyte morphology and myelin gene expression. Conversely, mutations associated with isolated hypomyelination (p.Val255Ile and p.Arg282Pro) and the severe combined phenotype (p.Asn414Lys) resulted in normal neuronal morphology but were associated with altered oligodendrocyte morphology, myelin gene expression, and microtubule dysfunction. The H-ABC mutation (p.Asp249Asn) that exhibits a combined neuronal and myelin phenotype had overlapping cellular defects involving both neuronal and oligodendrocyte cell types in vitro. Only mutations causing hypomyelination phenotypes showed altered microtubule dynamics and acted through a dominant toxic gain of function mechanism. The DYT4 mutation had no impact on microtubule dynamics suggesting a distinct mechanism of action. In summary, the different clinical phenotypes associated with TUBB4A reflect the selective and specific cellular effects of the causative mutations. Cellular specificity of disease pathogenesis is relevant to developing targeted treatments for this disabling condition.
2016-03-01 | TUBB4A-related hypomyelinating leukodystrophy: New insights from a series of 12 patients
Background Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) was first described in 2002. After the recent identification of TUBB4A mutation as the genetic basis of the disease, the clinical and neuroimaging phenotype related to TUBB4A mutations expanded, ranging from primary dystonia type 4 with normal MRI to severe H-ABC cases. Patients and methods The study included patients referred to us for an unclassified hypomyelinating leukodystrophy. We selected patients with deleterious heterozygous TUBB4A mutations. Molecular analysis of TUBB4A was performed on genomic DNA extracted from peripheral blood. Results The series included 12 patients (5 females and 7 males). Five patients carried the common mutation c.745G > A (p.Asp249Asn), while the remaining harbored different mutations. Three new mutations were found in 5 patients. Clinical and neuroimaging observations are described. A clear correlation between the clinical presentation and the genotype seems to be absent in our group of 12 patients. Conclusions TUBB4A-mutated patients manifest a comparable clinical and neuroimaging picture but they can differ from each other in terms of rate of disease progression. Extrapyramidal signs can be absent in the first stages of the disease, and a careful evaluation of MRI is fundamental to obtain the final diagnosis. From a therapeutic perspective a trial with l-dopa should be considered in all patients presenting extrapyramidal symptoms.
2006-06-29 | Effective treatment with levodopa and carbidopa for hypomyelination with atrophy of the basal ganglia and cerebellum.
Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare leukoencephalopathy presenting in the infantile period and characterized by diffuse cerebral hypomyelination, and atrophy of the basal ganglia and cerebellum. As patients with H-ABC lack remarkable laboratory findings, the diagnosis is based on brain magnetic resonance imaging findings alone. Only eight cases have been reported in the literature, and thus the natural course and treatment of this disease are not fully understood. We report a 35-month-old boy with H-ABC who had hemidystonia, hypomyelination, and cerebellar ataxia. We diagnosed H-ABC after considering a thorough differential diagnosis, excluding other diseases involving hemidystonia, hypomyelination, and cerebellar ataxia. Furthermore, technetium-99m ethyl cysteinate dimmer-single-photon emission computerized tomography (Tc-ECD-SPECT) and positron emission tomography with fluorodeoxyglucose (18)F (FDG-PET) revealed decreased blood flow and glucose metabolism in the bilateral lenticular nucleus, thalamus, and cerebellum. A peroral levodopa preparation containing carbidopa (levodopa-carbidopa) was effective at ameliorating and stopping the progression of the patient's dystonia (final effective doses: levodopa, 200 mg/day and carbidopa, 20 mg/day). This is the first case report of a Japanese patient with H-ABC and treatment for this disease. Levodopa-carbidopa may be an effective treatment for H-ABC.
oligonucleotides
2026-08-06 | Deletion of TUBB4A mitigates the oligodendrocyte and neuronal deficits in human iPSCs derived from individuals affected by H-ABC
Abstract TUBB4A -related leukodystrophy ( TUBB4A -LD) is a rare neurologic disorder with a broad spectrum of phenotypes, including severe early infantile encephalopathy, late infantile Hypomyelination with Atrophy of the Basal ganglia and Cerebellum (H-ABC), and milder late infantile forms. H-ABC is closely associated with a recurrent pathogenic variant, p.Asp249Asn, in the gene encoding tubulin beta class IVA (TUBB4A), a microtubule component. H-ABC presents with progressive dystonia, mobility loss, aphasia, and swallowing dysfunction in childhood. H-ABC results in cell-autonomous deficits in oligodendrocytes (OLs), cerebellar granule neurons, and medium spiny neurons (MSNs). Antisense oligonucleotides targeting Tubb4a can alleviate symptoms in H-ABC mouse models. However, the efficacy and safety of TUBB4A knockout in human cells remain poorly understood. We studied patient-derived TUBB4A D249N , TUBB4A KO , and control individual pluripotent stem cells (iPSCs). TUBB4A D249N iPSC-derived OLs failed to mature, showing less complexity and myelination, reduced microtubule acetylation and detyrosination. TUBB4A D249N iPSC-derived MSNs also showed impaired maturation and neurite extension. TUBB4A KO in mutant iPSCs reduced cellular deficits and was well tolerated. These findings support that suppression of TUBB4A could be a safe, effective therapy for TUBB4A - LD .
2024-08-27 | Therapeutic suppression of Tubb4a rescues H-ABC leukodystrophy
Abstract Hypomyelination and atrophy of basal ganglia and cerebellum (H-ABC) is a rare leukodystrophy associated with causal variants in β-tubulin 4A ( TUBB4A ). The recurring variant p.Asp249Asn (D249N) presents in infancy with dystonia, communication deficits, and loss of ambulation during the first decade of life. In this study, we characterized a genetic murine series ( Tubb4a KO/KO , Tubb4a D249N/+ , Tubb4a D249N/KO, and Tubb4a D249N/D249N ) to demonstrate that disease severity correlates with the expression of mutant Tubb4a and relative preservation of WT tubulin. To further evaluate the translational potential of Tubb4a suppression as a therapy in H-ABC, we identified a well-tolerated Tubb4a -targeted antisense oligonucleotide (ASO) candidate that selectively reduces Tubb4a in vitro and in vivo . Notably, single intracerebroventricular (i.c.v.) administration of ASO in postnatal Tubb4a D249N/KO mice drastically extends its lifespan, improves motor phenotypes, and reduces seizures. Neuropathologically, ASO treatment in Tubb4a D249N/KO mice restores myelin and oligodendrocyte survival. Furthermore, in vivo visual evoked potential latencies recover in ASO-treated Tubb4a D249N/KO mice. This is the first preclinical proof-of-concept for Tubb4a suppression via ASO as a disease-modifying therapy for H-ABC.
proteins
2025-10-19 | Exacerbation of absence seizures by central prolactin in female taiep rats: An animal model of epilepsy-prone leukodystrophy.
Absence seizures are a type of generalized epilepsy characterized by spike-wave discharges (SWDs) in the electroencephalogram (EEG). This condition affects girls more frequently than boys and has a worse prognosis in women during puberty and adulthood. These characteristics of sexual dimorphism and age predominance could be attributed to changes in plasma hormone levels during development, particularly during puberty, which can modulate the cortico-thalamic circuit responsible for generating and sustaining SWDs. Prolactin is a peptide hormone secreted by adenohypophysis, exhibits sexual dimorphism and undergoes an increase during puberty. In this study, we employed female taiep rats, a well-validated animal model of leukodystrophy known as hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). This model has a sexually dimorphic pattern of SWDs, with males exhibiting greater susceptibility to the condition. The rats were ovariectomized and electrodes were implanted for EEGs and a stainless-steel cannula for administration of rat prolactin via intracerebroventricular (i.c.v.) injection. Five 12-hour EEGs were performed with fixed 48-hour start intervals: the control EEG followed by i.c.v. prolactin administration at doses of 0.5, 1, 2, or 4 μg/2 μL. The frequency of SWDs increased significantly with the 2 and 4 μg/2 μL doses of prolactin. The mean duration of SWDs increased significantly with all doses evaluated, with the greatest effect observed 6 h after 4 μg/2 μL of prolactin, which doubled the mean duration obtained in control conditions. Additionally, prolactin 4 μg/2 μL significantly decreased the latency to the first SWDs. We propose that prolactin is capable of neuromodulating the thalamo-cortical circuit responsible for spike-wave discharges.
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Drug Discovery Landscape
1 orphan drug designation for Hypomyelination with atrophy of basal ganglia and cerebellum.
1 orphan drug designation for Hypomyelination with atrophy of basal ganglia and cerebellum.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
single stranded, synthetic, hybrid RNA/DNA antisense oligonucleotide (ASO) gapmer targeting the TUBB4A gene | oligonucleotides | FDA | — | SynaptixBio Ltd. |
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