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Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C.

Starke S, Meinke P, Camozzi D, Mattioli E, Pfaeffle R, Siekmeyer M, Hirsch W, Horn LC, Paasch U, Mitter D, Lattanzi G, Wehnert M, Kiess W - Aging (Albany NY) (2013)

Bottom Line: A homozygousLMNA mutation c.1303C>T (p.R435C) was found by Sanger sequencing.Haplotyping revealed a partial uniparental disomy of chromosome 1 (1q21.3 to 1q23.1) including the LMNA gene.The follow-up of the complete clinical course in the patient combined with functional studies showed for the first time that a progressive loss of lamin A rather than abnormal accumulation of prelamin A species could be a pathophysiological mechanism in progeroid laminopathies, which leads to DNA repair deficiency accompanied by advancing tissue degeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Women and Child Health, Hospital for Children and Adolescents, Centre of Pediatric Research, University Hospital, University of Leipzig, Leipzig, Germany. Sven.Starke@medizin.uni‐leipzig.de

ABSTRACT
The clinical course of a female patient affected by a progeroid syndrome with Restrictive Dermopathy (RD)-like features was followed up. Besides missing hairiness, stagnating weight and growth, RD-like features including progressive skin swelling and solidification, acrocontractures, osteolysis and muscular hypotension were observed until the patient died at the age of 11 months. A homozygousLMNA mutation c.1303C>T (p.R435C) was found by Sanger sequencing. Haplotyping revealed a partial uniparental disomy of chromosome 1 (1q21.3 to 1q23.1) including the LMNA gene. In contrast to reported RD patients with LMNA mutations, LMNA p.R435C is not located at the cleavage site necessary for processing of prelamin A by ZMPSTE24 and leads to a distinct phenotype combining clinical features of Restrictive Dermopathy, Mandibuloacral Dysplasia and Hutchinson-Gilford Progeria. Functionally, LMNA p.R435C is associated with increasing DNA double strand breaks and decreased recruitment of P53 binding protein 1 (53BP1) to DNA-damage sites indicating delayed DNA repair. The follow-up of the complete clinical course in the patient combined with functional studies showed for the first time that a progressive loss of lamin A rather than abnormal accumulation of prelamin A species could be a pathophysiological mechanism in progeroid laminopathies, which leads to DNA repair deficiency accompanied by advancing tissue degeneration.

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Related in: MedlinePlus

The patient at the age of 11 months: (a) microstomia, fixed in an o-shaped position (b) prominent superficial scalp veins, dysplastic auricels, microretrognathia. (c-e) acrocontractures. (f)„rocker bottom“ foot with prominent calcaneus and rounded bottom.
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Figure 3: The patient at the age of 11 months: (a) microstomia, fixed in an o-shaped position (b) prominent superficial scalp veins, dysplastic auricels, microretrognathia. (c-e) acrocontractures. (f)„rocker bottom“ foot with prominent calcaneus and rounded bottom.

Mentions: We report on an infant girl born at term by caesarian section due to nuchal cord after normal course of pregnancy. At newborn age, she was small for gestational age (birth weight below 3rd percentile, birth length below 10th percentile, head circumference below 3rd percentile). She presented with muscular hypotension sucking weakness and slightly impaired swallowing. At the age of two months, skin turgors and a generalized failure to thrive were noticed. Weight gain had been stagnating since then on, length and head circumference growth remained below 3rd percentile (Fig.1). At the age of four months, her skin appeared sclerotic and turgid with thereby initiating acrocontractures; the body fat and body hair were almost absent, and the child suffered from generalized hyperhidrosis, pruritus and touch sensitivity. As an attempt of treatment, a short course of steroids was given tentatively. However, the disease underwent continuous progression and syndromal features, including microstomia, microretrognathia, dysplastic auricles, small pinched nose, prominent superficial scalp veins, hands in claw-hand position and rocker bottom feet, were advancing (Fig.2a, b and 3).


Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C.

Starke S, Meinke P, Camozzi D, Mattioli E, Pfaeffle R, Siekmeyer M, Hirsch W, Horn LC, Paasch U, Mitter D, Lattanzi G, Wehnert M, Kiess W - Aging (Albany NY) (2013)

The patient at the age of 11 months: (a) microstomia, fixed in an o-shaped position (b) prominent superficial scalp veins, dysplastic auricels, microretrognathia. (c-e) acrocontractures. (f)„rocker bottom“ foot with prominent calcaneus and rounded bottom.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824411&req=5

Figure 3: The patient at the age of 11 months: (a) microstomia, fixed in an o-shaped position (b) prominent superficial scalp veins, dysplastic auricels, microretrognathia. (c-e) acrocontractures. (f)„rocker bottom“ foot with prominent calcaneus and rounded bottom.
Mentions: We report on an infant girl born at term by caesarian section due to nuchal cord after normal course of pregnancy. At newborn age, she was small for gestational age (birth weight below 3rd percentile, birth length below 10th percentile, head circumference below 3rd percentile). She presented with muscular hypotension sucking weakness and slightly impaired swallowing. At the age of two months, skin turgors and a generalized failure to thrive were noticed. Weight gain had been stagnating since then on, length and head circumference growth remained below 3rd percentile (Fig.1). At the age of four months, her skin appeared sclerotic and turgid with thereby initiating acrocontractures; the body fat and body hair were almost absent, and the child suffered from generalized hyperhidrosis, pruritus and touch sensitivity. As an attempt of treatment, a short course of steroids was given tentatively. However, the disease underwent continuous progression and syndromal features, including microstomia, microretrognathia, dysplastic auricles, small pinched nose, prominent superficial scalp veins, hands in claw-hand position and rocker bottom feet, were advancing (Fig.2a, b and 3).

Bottom Line: A homozygousLMNA mutation c.1303C>T (p.R435C) was found by Sanger sequencing.Haplotyping revealed a partial uniparental disomy of chromosome 1 (1q21.3 to 1q23.1) including the LMNA gene.The follow-up of the complete clinical course in the patient combined with functional studies showed for the first time that a progressive loss of lamin A rather than abnormal accumulation of prelamin A species could be a pathophysiological mechanism in progeroid laminopathies, which leads to DNA repair deficiency accompanied by advancing tissue degeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Women and Child Health, Hospital for Children and Adolescents, Centre of Pediatric Research, University Hospital, University of Leipzig, Leipzig, Germany. Sven.Starke@medizin.uni‐leipzig.de

ABSTRACT
The clinical course of a female patient affected by a progeroid syndrome with Restrictive Dermopathy (RD)-like features was followed up. Besides missing hairiness, stagnating weight and growth, RD-like features including progressive skin swelling and solidification, acrocontractures, osteolysis and muscular hypotension were observed until the patient died at the age of 11 months. A homozygousLMNA mutation c.1303C>T (p.R435C) was found by Sanger sequencing. Haplotyping revealed a partial uniparental disomy of chromosome 1 (1q21.3 to 1q23.1) including the LMNA gene. In contrast to reported RD patients with LMNA mutations, LMNA p.R435C is not located at the cleavage site necessary for processing of prelamin A by ZMPSTE24 and leads to a distinct phenotype combining clinical features of Restrictive Dermopathy, Mandibuloacral Dysplasia and Hutchinson-Gilford Progeria. Functionally, LMNA p.R435C is associated with increasing DNA double strand breaks and decreased recruitment of P53 binding protein 1 (53BP1) to DNA-damage sites indicating delayed DNA repair. The follow-up of the complete clinical course in the patient combined with functional studies showed for the first time that a progressive loss of lamin A rather than abnormal accumulation of prelamin A species could be a pathophysiological mechanism in progeroid laminopathies, which leads to DNA repair deficiency accompanied by advancing tissue degeneration.

Show MeSH
Related in: MedlinePlus