Advances in Experimental Medicine and Biology, 2017
Hepatorenal tyrosinaemia (HT1) is a serious condition that used to be fatal before the advent of ... more Hepatorenal tyrosinaemia (HT1) is a serious condition that used to be fatal before the advent of nitisinone (NTBC, Orfadine®) as a therapeutic option. We have recently shown that selective screening is inadequate as initial symptoms are often uncharacteristic which leads to a considerable delay in diagnosis and treatment. This has a negative impact on morbidity and mortality as well as long-term outcome. For example, the odds ratio to develop hepatocellular carcinoma is 12.7 when treatment is initiated after the first birthday compared to start of treatment in the neonatal period. Timely diagnosis is only possible when neonatal mass screening is operational. HT1 meets all the criteria for neonatal mass screening at a clinical and analytical level. The natural course of the disease is well known, clinically there is a latent phase in most patients when presymptomatic treatment can be initiated. There are no mild phenotypes which do not require treatment. Using succinylacetone as the screening parameter a highly specific and sensitive test is available with acceptable financial burden. Neonatal mass screening for HT1 is acceptable to the target population as it can be performed simultaneously with the already existing screening tests in dried blood, there are no false negative and false positive cases and the financial burden to the health system is moderate. An efficient treatment is available with nitisinone and protein-reduced diet supplemented with special amino acid mixtures. Despite compelling evidence in favour of a neonatal mass screening for HT1 only 57% of European centres taking part in our recent cross-sectional study have included HT1 in their newborn screening programme.
Topical application of minoxidil can boost hair growth in female baldness. As this substance is a... more Topical application of minoxidil can boost hair growth in female baldness. As this substance is a vasodilator which is absorbed and activated in the scalp it may lead to local vasodilation with headache and dizziness. It is available as over-the counter selfmedication. It is sometimes used as a 'lifestyle' substance for boosting hair growth by adolescents. Careful history taking is essential to identify this substance and should be considered in patients with unexplained headache and dizziness. Simple discontinuation will resolve the symptoms.
Introduction We describe three boys who were referred for neurological work-up of a tottering gai... more Introduction We describe three boys who were referred for neurological work-up of a tottering gait and in whom we diagnosed bone diseases, namely, Camurati-Engelmann disease, cartilaginous exostoses and a stress fracture as the underlying causes for the gait-disturbances. Conclusion “Non-neurologic disorders” must be considered even if pain is not a leading symptom in gait disturbances.
Fetal infection is associated with considerable perinatal morbidity. Dysfunction of human umbilic... more Fetal infection is associated with considerable perinatal morbidity. Dysfunction of human umbilical venous endothelial cells (HUVEC) may compromise fetal blood supply from the placenta. HUVECs were incubated with one of the key inflammatory mediators, lipopolysaccharides (LPS), and activities of respiratory chain enzymes were measured. Based on gestational age, HUVEC were divided into a mature and two premature groups from otherwise uncomplicated pregnancies (four patients each) and incubated for 1, 6, or 12 hours with LPS (100 ng/mL), respectively, incubation without LPS served as a control. We analyzed the activities of respiratory chain enzymes and citrate synthase as a mitochondrial marker spectrophotometrically. No significant differences in respiratory chain activities between the LPS-incubated cells and internal controls could be observed. However, we were able to demonstrate significant differences depending on gestational age: respiratory chain complex IV (p
Congenital ornithine transcarbamylase deficiency (OTCD, OMIM 311250, Xp21.1) in humans results in... more Congenital ornithine transcarbamylase deficiency (OTCD, OMIM 311250, Xp21.1) in humans results in hyperammonaemia with subsequent neurological symptoms including hypotonia, seizures and mental retardation. At the age of 3 years a hyperkinetic-hyperactive behaviour disorder of unknown origin was diagnosed in our female patient. The girl, ultimately diagnosed as having OTCD presented at the age of 6 years with an episode of feverassociated metabolic stroke including coma, epilepsy and further neurological symptoms due to hyperammonaemia. The pattern of plasma amino acids, the elevated level of orotic acid in urine and mutation analysis confirmed the diagnosis of OTCD. The possibility of early diagnosis and therapy of a disease which otherwise leads to severe neurological and psychiatric sequelae emphasizes the importance of precise evaluation of a possible organic cause for hyperkinetic-hyperactive behaviour disorders. This case of late-onset OTCD demonstrates that total recovery is possible even after a long comaepisode with slow reconvalescence. (J Pediatr Neurol 2004; 2(2): 97-100).
ornithine transcarbamylase deficiency (OTCD, OMIM 311250, Xp21.1) in humans results in hyperammon... more ornithine transcarbamylase deficiency (OTCD, OMIM 311250, Xp21.1) in humans results in hyperammonaemia with subsequent neurological symptoms including hypotonia, seizures and mental retardation. At the age of 3 years a hyperkinetic-hyperactive behaviour disorder of unknown origin was diagnosed in our female patient. The girl, ultimately diagnosed as having OTCD presented at the age of 6 years with an episode of feverassociated metabolic stroke including coma, epilepsy and further neurological symptoms due to hyperammonaemia. The pattern of plasma amino acids, the elevated level of orotic acid in urine and mutation analysis confirmed the diagnosis of OTCD. The possibility of early diagnosis and therapy of a disease which otherwise leads to severe neurological and psychiatric sequelae emphasizes the importance of precise evaluation of a possible organic cause for hyperkinetic-hyperactive behaviour disorders. This case of late-onset OTCD demonstrates that total recovery is possible even after a long comaepisode with slow reconvalescence. (J Pediatr Neurol 2004; 2(2): 97-100).
Aufgrund einer fruhzeitigen Diagnostik (z. B. Neugeborenenscreening), eines fruhzeitigen Therapie... more Aufgrund einer fruhzeitigen Diagnostik (z. B. Neugeborenenscreening), eines fruhzeitigen Therapiebeginns und verbesserter Therapieoptionen erreichen heutzutage mehr und mehr Patienten mit angeborenen Stoffwechselkrankheiten das Erwachsenenalter. Im Rahmen des Therapiemonitorings sind spezielle Laboruntersuchungen auch weiterhin integraler Bestandteil der klinischen Versorgung dieser Patienten. Spezielle Labormethoden sind aber auch fur die Diagnostik/Differenzialdiagnostik von Stoffwechselkrankheiten bei Erwachsenen von Bedeutung. Personen mit einer spatmanifesten Stoffwechselkrankheit entwickeln in der Regel unter dem Einfluss eines eher milden Gendefekts erst im Jugend- oder Erwachsenenalter eine hinreichende Symptomatik, um eine »Stoffwechseldiagnostik« in Gang zu setzen. Im Gegensatz zu solchen langsam progredienten Krankheitsbildern kann die Symptomatik aber auch dramatisch verlaufen. In solchen Fallen ist der vorliegende milde Gendefekt eine notwendige, aber offenbar nicht hinreichende Bedingung fur das Auftreten von Symptomen. Vielmehr mussen zusatzliche ausere Faktoren wie Katabolie (bei interkurrenten Erkrankungen, Operationen, korperlicher Belastung oder prolongierten Hungerzustanden) oder die Aufnahme von »zu viel« Protein oder von bestimmten Kohlenhydraten mit der Nahrung als Trigger hinzukommen. In solchen Situationen kommt es zu einer erheblichen Belastung des Organismus mit toxischen Metaboliten wie Ammoniak oder organischen Sauren, die er infolge des Gendefekts nicht weiter abbauen kann und die eine krisenhafte »Stoffwechselentgleisung« hervorrufen konnen.
hepatic lipid peroxidation. Results: Hepatic Hamp1 mRNA expression was significantly decreased (p... more hepatic lipid peroxidation. Results: Hepatic Hamp1 mRNA expression was significantly decreased (p < 0.003) and duodenal ferroportin expression was increased (p < 0.0003), in alcohol-fed wild-type mice (n = 7) at 8 weeks. Consistent with the genetic defect, Hamp1 mRNA was decreased (3.5 fold; p < 0.0001) in Hfe −/ − mice (n = 10) fed the control diet compared to WT and this was further suppressed (6.4 fold; p < 0.0001) in alcohol-fed Hfe −/ − mice. Alcohol consumption did not result in a decrease in either pCAAT enhancing binding factor alpha or pSTAT3. Consistent with a hypoxic response, hypoxic inducible factor alpha protein levels were elevated in alcohol fed wild-type animals compared to controls (2.9 fold; p < 0.001). Liver injury, observed in all alcohol-fed mice, was exacerbated by iron in Hfe −/ − mice at 8 weeks. Conclusion: An alcohol-induced hypoxic response may regulate Hamp1 gene expression. A co-toxic effect of alcohol and iron exacerbates liver injury and the demonstration that alcohol consumption further suppresses Hamp1 expression in Hfe −/ − mice suggests that alcohol may also modulate Hamp1 gene expression independently of the HFE pathway.
Many proteins and lipid components are organized within membrane microdomains, known as lipid raf... more Many proteins and lipid components are organized within membrane microdomains, known as lipid rafts (LR). LR are cholesterol- and sphingolipid-rich membranes resistant to non-ionic detergents. In Niemann-Pick type C1 (NPC1), a neurovisceral lysosomal storage disease, entrapment of cholesterol and sphingolipids occurs and may lead to alterations in LR composition. We investigate the LR status in fibroblasts derived from a patient with NPC1 and analyze the trafficking profiles of a typical LR-associated membrane protein, dipeptidylpeptidase IV (DPPIV). Sucrose density gradients of Triton X-100 cellular lysates revealed a substantial shift of the LR-marker flotillin2 in NPC fibroblasts from the floating LR fractions to the detergent-soluble membranes. Notably, the cell surface expression of DPPIV increased significantly by 2-fold in NPC1 cells, while the overall protein level of DPPIV remained constant. FACS analysis corroborated the increase of DPPIV at the cell surface. This accumulation is the result of d...
Article history: Received 21 October 2016 Accepted 2 November 2016 Available online xxxx the L-ar... more Article history: Received 21 October 2016 Accepted 2 November 2016 Available online xxxx the L-arginine/NO pathway in the MELAS syndrome is insufficiently explored and controversial. Further systematic investigations in larger patient cohorts are necessary in order to address remaining issues properly [1]. Unfortunately, Finsterer and Zarrouk-Mahjoub [1] neither clarified any of the reported issues in our case work up [2] nor added to the understanding of the L-arginine/NO pathway in the MELAS syn-
Background: Mucopolysaccharidosis (MPS) and mucolipidosis (ML) are groups of rare lysosomal disor... more Background: Mucopolysaccharidosis (MPS) and mucolipidosis (ML) are groups of rare lysosomal disorders, resulting in progressive multi-organ disease including severe skeletal affection. There are only few reports on puberty, fertility and pregnancy in patients with MPS/ML. The aim of this survey was to obtain more insight into female fertility, pregnancy and the peripartal period in MPS/ML patients. Methods: 42 female patients ≥16 yrs. (17-63 yrs) with MPS I/III/IV/VI or ML III from 7 German-speaking metabolic centers participated in this survey (questionnaire with 65 questions on fertility and pregnancy). Results: Beginning of pubarche was observed with 13 ± 3.7 yrs., the mean age at menarche was 14 ± 1.8 yrs., breast development ended at 16 ± 2.2 yrs. and adult body height was reached at 16 ± 4.1 yrs. Menopause started at the age of 47.5 ± 2.9 yrs. (n = 4). Eleven pregnancies in eight females, all after spontaneous conception, passed without severe complications. At start of pregnancy, mothers were aged 28 ± 4.2 yrs. and were 145 ± 20 cm tall. Five females gave birth to 1 child, 1 to 2 children and 1 to 3 children. One pregnancy was terminated by interruption. Three women received enzyme replacement therapy (ERT) during pregnancy. Delivery was uneventful in all females and occurred after 38 ± 1.5 weeks of pregnancy (3/10 spontaneously, 7/10 Caesarean section). All children were healthy at birth. Five mothers were breastfeeding, 3/5 while on ERT. Discussion: These data demonstrate that pubertal development and fertility in females with MPS/ML do not show significant differences from healthy average population. Pregnancy and delivery were without major complications. All children of MPS mothers were born healthy without malformations. Weight, height and head circumference of the newborns were below the 50th percentile. ERT during pregnancy seems to have no negative impact on fetal development.
in-frame deletions, three clinical subgroups arise that differ significantly regarding main clini... more in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domainspecific functions of NBAS.
Advances in Experimental Medicine and Biology, 2017
Hepatorenal tyrosinaemia (HT1) is a serious condition that used to be fatal before the advent of ... more Hepatorenal tyrosinaemia (HT1) is a serious condition that used to be fatal before the advent of nitisinone (NTBC, Orfadine®) as a therapeutic option. We have recently shown that selective screening is inadequate as initial symptoms are often uncharacteristic which leads to a considerable delay in diagnosis and treatment. This has a negative impact on morbidity and mortality as well as long-term outcome. For example, the odds ratio to develop hepatocellular carcinoma is 12.7 when treatment is initiated after the first birthday compared to start of treatment in the neonatal period. Timely diagnosis is only possible when neonatal mass screening is operational. HT1 meets all the criteria for neonatal mass screening at a clinical and analytical level. The natural course of the disease is well known, clinically there is a latent phase in most patients when presymptomatic treatment can be initiated. There are no mild phenotypes which do not require treatment. Using succinylacetone as the screening parameter a highly specific and sensitive test is available with acceptable financial burden. Neonatal mass screening for HT1 is acceptable to the target population as it can be performed simultaneously with the already existing screening tests in dried blood, there are no false negative and false positive cases and the financial burden to the health system is moderate. An efficient treatment is available with nitisinone and protein-reduced diet supplemented with special amino acid mixtures. Despite compelling evidence in favour of a neonatal mass screening for HT1 only 57% of European centres taking part in our recent cross-sectional study have included HT1 in their newborn screening programme.
Topical application of minoxidil can boost hair growth in female baldness. As this substance is a... more Topical application of minoxidil can boost hair growth in female baldness. As this substance is a vasodilator which is absorbed and activated in the scalp it may lead to local vasodilation with headache and dizziness. It is available as over-the counter selfmedication. It is sometimes used as a 'lifestyle' substance for boosting hair growth by adolescents. Careful history taking is essential to identify this substance and should be considered in patients with unexplained headache and dizziness. Simple discontinuation will resolve the symptoms.
Introduction We describe three boys who were referred for neurological work-up of a tottering gai... more Introduction We describe three boys who were referred for neurological work-up of a tottering gait and in whom we diagnosed bone diseases, namely, Camurati-Engelmann disease, cartilaginous exostoses and a stress fracture as the underlying causes for the gait-disturbances. Conclusion “Non-neurologic disorders” must be considered even if pain is not a leading symptom in gait disturbances.
Fetal infection is associated with considerable perinatal morbidity. Dysfunction of human umbilic... more Fetal infection is associated with considerable perinatal morbidity. Dysfunction of human umbilical venous endothelial cells (HUVEC) may compromise fetal blood supply from the placenta. HUVECs were incubated with one of the key inflammatory mediators, lipopolysaccharides (LPS), and activities of respiratory chain enzymes were measured. Based on gestational age, HUVEC were divided into a mature and two premature groups from otherwise uncomplicated pregnancies (four patients each) and incubated for 1, 6, or 12 hours with LPS (100 ng/mL), respectively, incubation without LPS served as a control. We analyzed the activities of respiratory chain enzymes and citrate synthase as a mitochondrial marker spectrophotometrically. No significant differences in respiratory chain activities between the LPS-incubated cells and internal controls could be observed. However, we were able to demonstrate significant differences depending on gestational age: respiratory chain complex IV (p
Congenital ornithine transcarbamylase deficiency (OTCD, OMIM 311250, Xp21.1) in humans results in... more Congenital ornithine transcarbamylase deficiency (OTCD, OMIM 311250, Xp21.1) in humans results in hyperammonaemia with subsequent neurological symptoms including hypotonia, seizures and mental retardation. At the age of 3 years a hyperkinetic-hyperactive behaviour disorder of unknown origin was diagnosed in our female patient. The girl, ultimately diagnosed as having OTCD presented at the age of 6 years with an episode of feverassociated metabolic stroke including coma, epilepsy and further neurological symptoms due to hyperammonaemia. The pattern of plasma amino acids, the elevated level of orotic acid in urine and mutation analysis confirmed the diagnosis of OTCD. The possibility of early diagnosis and therapy of a disease which otherwise leads to severe neurological and psychiatric sequelae emphasizes the importance of precise evaluation of a possible organic cause for hyperkinetic-hyperactive behaviour disorders. This case of late-onset OTCD demonstrates that total recovery is possible even after a long comaepisode with slow reconvalescence. (J Pediatr Neurol 2004; 2(2): 97-100).
ornithine transcarbamylase deficiency (OTCD, OMIM 311250, Xp21.1) in humans results in hyperammon... more ornithine transcarbamylase deficiency (OTCD, OMIM 311250, Xp21.1) in humans results in hyperammonaemia with subsequent neurological symptoms including hypotonia, seizures and mental retardation. At the age of 3 years a hyperkinetic-hyperactive behaviour disorder of unknown origin was diagnosed in our female patient. The girl, ultimately diagnosed as having OTCD presented at the age of 6 years with an episode of feverassociated metabolic stroke including coma, epilepsy and further neurological symptoms due to hyperammonaemia. The pattern of plasma amino acids, the elevated level of orotic acid in urine and mutation analysis confirmed the diagnosis of OTCD. The possibility of early diagnosis and therapy of a disease which otherwise leads to severe neurological and psychiatric sequelae emphasizes the importance of precise evaluation of a possible organic cause for hyperkinetic-hyperactive behaviour disorders. This case of late-onset OTCD demonstrates that total recovery is possible even after a long comaepisode with slow reconvalescence. (J Pediatr Neurol 2004; 2(2): 97-100).
Aufgrund einer fruhzeitigen Diagnostik (z. B. Neugeborenenscreening), eines fruhzeitigen Therapie... more Aufgrund einer fruhzeitigen Diagnostik (z. B. Neugeborenenscreening), eines fruhzeitigen Therapiebeginns und verbesserter Therapieoptionen erreichen heutzutage mehr und mehr Patienten mit angeborenen Stoffwechselkrankheiten das Erwachsenenalter. Im Rahmen des Therapiemonitorings sind spezielle Laboruntersuchungen auch weiterhin integraler Bestandteil der klinischen Versorgung dieser Patienten. Spezielle Labormethoden sind aber auch fur die Diagnostik/Differenzialdiagnostik von Stoffwechselkrankheiten bei Erwachsenen von Bedeutung. Personen mit einer spatmanifesten Stoffwechselkrankheit entwickeln in der Regel unter dem Einfluss eines eher milden Gendefekts erst im Jugend- oder Erwachsenenalter eine hinreichende Symptomatik, um eine »Stoffwechseldiagnostik« in Gang zu setzen. Im Gegensatz zu solchen langsam progredienten Krankheitsbildern kann die Symptomatik aber auch dramatisch verlaufen. In solchen Fallen ist der vorliegende milde Gendefekt eine notwendige, aber offenbar nicht hinreichende Bedingung fur das Auftreten von Symptomen. Vielmehr mussen zusatzliche ausere Faktoren wie Katabolie (bei interkurrenten Erkrankungen, Operationen, korperlicher Belastung oder prolongierten Hungerzustanden) oder die Aufnahme von »zu viel« Protein oder von bestimmten Kohlenhydraten mit der Nahrung als Trigger hinzukommen. In solchen Situationen kommt es zu einer erheblichen Belastung des Organismus mit toxischen Metaboliten wie Ammoniak oder organischen Sauren, die er infolge des Gendefekts nicht weiter abbauen kann und die eine krisenhafte »Stoffwechselentgleisung« hervorrufen konnen.
hepatic lipid peroxidation. Results: Hepatic Hamp1 mRNA expression was significantly decreased (p... more hepatic lipid peroxidation. Results: Hepatic Hamp1 mRNA expression was significantly decreased (p < 0.003) and duodenal ferroportin expression was increased (p < 0.0003), in alcohol-fed wild-type mice (n = 7) at 8 weeks. Consistent with the genetic defect, Hamp1 mRNA was decreased (3.5 fold; p < 0.0001) in Hfe −/ − mice (n = 10) fed the control diet compared to WT and this was further suppressed (6.4 fold; p < 0.0001) in alcohol-fed Hfe −/ − mice. Alcohol consumption did not result in a decrease in either pCAAT enhancing binding factor alpha or pSTAT3. Consistent with a hypoxic response, hypoxic inducible factor alpha protein levels were elevated in alcohol fed wild-type animals compared to controls (2.9 fold; p < 0.001). Liver injury, observed in all alcohol-fed mice, was exacerbated by iron in Hfe −/ − mice at 8 weeks. Conclusion: An alcohol-induced hypoxic response may regulate Hamp1 gene expression. A co-toxic effect of alcohol and iron exacerbates liver injury and the demonstration that alcohol consumption further suppresses Hamp1 expression in Hfe −/ − mice suggests that alcohol may also modulate Hamp1 gene expression independently of the HFE pathway.
Many proteins and lipid components are organized within membrane microdomains, known as lipid raf... more Many proteins and lipid components are organized within membrane microdomains, known as lipid rafts (LR). LR are cholesterol- and sphingolipid-rich membranes resistant to non-ionic detergents. In Niemann-Pick type C1 (NPC1), a neurovisceral lysosomal storage disease, entrapment of cholesterol and sphingolipids occurs and may lead to alterations in LR composition. We investigate the LR status in fibroblasts derived from a patient with NPC1 and analyze the trafficking profiles of a typical LR-associated membrane protein, dipeptidylpeptidase IV (DPPIV). Sucrose density gradients of Triton X-100 cellular lysates revealed a substantial shift of the LR-marker flotillin2 in NPC fibroblasts from the floating LR fractions to the detergent-soluble membranes. Notably, the cell surface expression of DPPIV increased significantly by 2-fold in NPC1 cells, while the overall protein level of DPPIV remained constant. FACS analysis corroborated the increase of DPPIV at the cell surface. This accumulation is the result of d...
Article history: Received 21 October 2016 Accepted 2 November 2016 Available online xxxx the L-ar... more Article history: Received 21 October 2016 Accepted 2 November 2016 Available online xxxx the L-arginine/NO pathway in the MELAS syndrome is insufficiently explored and controversial. Further systematic investigations in larger patient cohorts are necessary in order to address remaining issues properly [1]. Unfortunately, Finsterer and Zarrouk-Mahjoub [1] neither clarified any of the reported issues in our case work up [2] nor added to the understanding of the L-arginine/NO pathway in the MELAS syn-
Background: Mucopolysaccharidosis (MPS) and mucolipidosis (ML) are groups of rare lysosomal disor... more Background: Mucopolysaccharidosis (MPS) and mucolipidosis (ML) are groups of rare lysosomal disorders, resulting in progressive multi-organ disease including severe skeletal affection. There are only few reports on puberty, fertility and pregnancy in patients with MPS/ML. The aim of this survey was to obtain more insight into female fertility, pregnancy and the peripartal period in MPS/ML patients. Methods: 42 female patients ≥16 yrs. (17-63 yrs) with MPS I/III/IV/VI or ML III from 7 German-speaking metabolic centers participated in this survey (questionnaire with 65 questions on fertility and pregnancy). Results: Beginning of pubarche was observed with 13 ± 3.7 yrs., the mean age at menarche was 14 ± 1.8 yrs., breast development ended at 16 ± 2.2 yrs. and adult body height was reached at 16 ± 4.1 yrs. Menopause started at the age of 47.5 ± 2.9 yrs. (n = 4). Eleven pregnancies in eight females, all after spontaneous conception, passed without severe complications. At start of pregnancy, mothers were aged 28 ± 4.2 yrs. and were 145 ± 20 cm tall. Five females gave birth to 1 child, 1 to 2 children and 1 to 3 children. One pregnancy was terminated by interruption. Three women received enzyme replacement therapy (ERT) during pregnancy. Delivery was uneventful in all females and occurred after 38 ± 1.5 weeks of pregnancy (3/10 spontaneously, 7/10 Caesarean section). All children were healthy at birth. Five mothers were breastfeeding, 3/5 while on ERT. Discussion: These data demonstrate that pubertal development and fertility in females with MPS/ML do not show significant differences from healthy average population. Pregnancy and delivery were without major complications. All children of MPS mothers were born healthy without malformations. Weight, height and head circumference of the newborns were below the 50th percentile. ERT during pregnancy seems to have no negative impact on fetal development.
in-frame deletions, three clinical subgroups arise that differ significantly regarding main clini... more in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domainspecific functions of NBAS.
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