Doenças Hereditárias do Metabolismo Manifestações cutâneas Margarida GonçaloDermatology – University Hospital and Faculty of Medicine

University of Coimbra – COIMBRA - PORTUGALII Curso Básico de DHM Coimbra, 5-7 dezembro 2016

DoençasHereditáriasdoMetabolismoManifestaçõescutâneas

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Impacto na qualidade de vida

DoençasHereditáriasdoMetabolismoManifestaçõescutâneas

A Stepwise Clinical Approach to Inherited Metabolic Diseases JTR CLARKE Division of Clinical & Metabolic Genetics, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada Proceedings 2004:9: 261-267

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REVIEW Open Access

ALG8-CDG: novel patients and review ofthe literatureMichaela Hˆ ck1, Karina Wegleiter1, Elisabeth Ralser1, Ursula Kiechl-Kohlendorfer1, Sabine Scholl-B¸ rgi2,Christine Fauth3, Elisabeth Steichen2, Karin Pichler2, Dirk J. Lefeber4, Gert Matthjis5, Liesbeth Keldermans5,Kathrin Maurer6, Johannes Zschocke3 and Daniela Karall2*

Abstract

Background: Since 1980, about 100 types of congenital disorders of glycosylation (CDG) have been reportedrepresenting an expanding group of inherited disorders. ALG8-CDG (= CDG-Ih) is one of the less frequently reportedtypes of CDG, maybe due to its severe multi-organ involvement with coagulation disturbances, edema, massivegastrointestinal protein loosing enteropathy, cataracts, and often early death. We report three additional patients,provide an update on two previously reported, and summarize features of ten patients reported in literature.

Results: Of 15 ALG8-CDG patients, three were homozygous and 12 compound heterozygous. There were multipleprenatal abnormalities in 6/12 patients. In 13/15, there were symptoms at birth, 9/15 died within 12 months. Birthweight was appropriate in 11/12, only one was small for gestational age. Prematurity was reported in 7/12. Hydropsfetalis was noticed in 3, edemas in 11/13; gastrointestinal symptoms in 9/14; structural brain pathology, psychomentalretardation, seizures, ataxia in 12/13, muscle hypotonia in 13/14. Common dysmorphic signs were: low set ears,macroglossia, hypertelorism, pes equinovarus, campto- and brachydactyly (13/15). In 10/11, there was coagulopathy,in 8/11 elevated transaminases; thrombocytopenia was present in 9/9. Eye involvement was reported in 9/14. CDGtypical skin involvement was reported in 8/13.

Conclusion: In ALG8-CDG, isoelectric focusing of transferrin in serum or plasma shows an abnormal sialotransferrinpattern. The diagnosis is confirmed by mutation analysis in ALG8; all patients reported so far had point mutations orsmall deletions. The prognosis is generally poor. Thus, a timely and correct diagnosis is important for counselling.

Keywords: Congenital disorders of glycosylation, Isoelectric focusing of transferrin, Hydrops fetalis, Cataract,Coagulopathy, Gastrointestinal symptoms

BackgroundCongenital disorders of glycosylation (CDG) involve arapidly growing group of metabolic diseases that arecaused by genetic defects in the synthesis of glycopro-teins [1]. The first two patients were diagnosed in 1980by the Belgian pediatrician Jaak Jaeken [2]. To date,some 100 CDG have been identified [1, 3] (with over700 patients reported worldwide), and about 50 of thesecan be identified via isoelectric focusing of transferrin[1, 3 ñ 5]. CDG have been divided in four groups: (1)disorders of protein N-glycosylation, (2) disorders ofprotein O-glycosylation, (3) disorders of lipid and GPI

(glycosylphosphatidylinositol) anchor glycosylation, and(4) disorders of multiple glycosylation pathways [5, 6]. De-fects in protein N-glycosylation are divided into two sub-groups: CDG-I disorders comprise defects in the glycansynthesis (cytosol and endoplasmic reticulum (ER)), andCDG-II disorders defects in glycan processing (Golgi ap-paratus) [1]. In 2008, Jaeken et al. proposed a nomencla-ture that refers to the gene name under the umbrellaname of CDG, e.g. PMM2-CDG, ALG8-CDG, etc. [7].CDG affect multiple organ systems, the severity of symp-toms is highly variable and it shows a broad clinicalspectrum with considerable overlap [1, 3].ALG8-CDG (OMIM #608104) is due to inactivating

mutations in the ALG8 gene encoding dolichyl-phosphate-glucose 1-mannose 9-N-acetylglucosamine (Dol-P-Glc:Glc

* Correspondence: daniela.karall@i-med.ac.at2Medical University of Innsbruck, Clinic for Pediatrics I, Inherited MetabolicDisorders, Anichstrasse 35, 6020 Innsbruck, AustriaFull list of author information is available at the end of the article

© 2015 Hˆ ck et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Hˆ ck et al. Orphanet Journal of Rare Diseases (2015) 10:73 DOI 10.1186/s13023-015-0289-7

Table 1 Findings in 15 patients with ALG8 deficiencySkladal[11]

Charlwood[14]

Chantret[8]

Schollen[15]

Eklund[9]

Vesela[16]

St̂ lting[17]

Sorte[18]

Funke [19]Kouwenberg[20]

Patients 1, 2, 5

Sex F M M F F M M F M F F M M M F

Prenatal Data

IUGR / / Yes / Yes No No No No No Yes No No No No

Oligohydramnios / / Yes / Yes No No Yes No No No No Yes Yes No

Hydrops fetalis / / ND / / / / Yes No No / No Yes Yes No

Neonatal data

Weeks ofgestation

/ 36 w (CS) 35 w (CS) / / 35 w 37 w 29 w (CS) At term At term 39 w (CS) 35 w 34 w (CS) 35 w (CS) 37 w (CS)

Birth weight / 2,590 g 2,280 g / / 2,920 g 3,070 g 1,420 g 3,980 g 3,680 g 2,210 g 2,920 g 2,570 g 2,700 g 3,080 g

Clinicalsymptoms

Ascites/edemas / Yes Yes Yes Yes Yes Yes No No Yes Yes Yes Yes Yes

Onset of firstsymptoms

Frombirth

Frombirth

4 months Frombirth

8 weeks Frombirth

Frombirth

Frombirth

Frombirth

Frombirth

Frombirth

Frombirth

Frombirth

Frombirth

Dysmorphism Yes Yes No Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes

Gastrointestinalsymptoms

/ Yes Yes No Yes Yes Yes No No Yes Yes No Yes Yes

Braininvolvement

Yes Yes No / Yes Yes Yes Yes Yes Yes Yes / Yes Yes

Hypotonia / Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Skin involvement / Yes No / Yes No No Yes Yes Yes Yes No No Yes

Eye symptoms Cataract No Retinopathy / No Cataract Opticatrophy

No No Nystagmus No Cataract Cataract Cataract

Laboratory data

Thrombocytopenia / Yes / Yes Yes Yes Yes / / Yes Yes / Yes Yes

Coagulopathy Yes Yes Yes Yes ND Yes Yes / / Yes Yes / Yes No

Hyponatremia / Yes / Yes Yes Yes / / / / Yes Yes Yes Yes

Increasedtransaminases

Yes Yes No / Yes Yes No / / Yes Yes / Yes No

Hˆck

etal.O

rphanetJournalofRare

Diseases

(2015) 10:73 Page

3of8

involvement

Findings in 15 patients with ALG8 deficiency

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parameters and thyroid function tests) were normal. Overthe next weeks, the girl deteriorated progressively with re-current episodes of apneas often combined with bradycar-dia. Electroencephalogram (EEG) showed a pathologicalbrain wave pattern with decreased brain activity. On day38 of life, a pale skin and apneas were noted, with ventricu-lar tachycardia. The girl died from cardiovascular arrest.

MethodsSerum transferrin isoelectrofocusing was performed as re-ported [12]. Mutation analysis of the PMM2 and ALG8genes was performed according to standard methods [1, 13].In CDG, enzyme analyses are not available for all types

of defects in the pathway. When enzymatic analysislacks, lipid-linked oligosaccharides (LLO) in fibroblasts

Fig. 1 a,b Patient 4 at the age of 10 months - floppy infant, with multiple dysmorphic features such as a prominent forehead, wide fontanelle,macroglossia, dysplastic ears, high palate, inverted nipples, short fingers and toes and a pale mottled skin, ì fat padsî on arms and thighs [11]

Fig. 2 a,b Patient 5 at the age of 20 days - floppy infant, with intermittent dystonic posturing, and multiple dysmorphic features such as anabnormal fat distribution on arms and thighs, macroglossia, low-set ears, additionally, cataracts and persisting primary vitreous artery were present

Hˆ ck et al. Orphanet Journal of Rare Diseases (2015) 10:73 Page 5 of 8parameters and thyroid function tests) were normal. Overthe next weeks, the girl deteriorated progressively with re-current episodes of apneas often combined with bradycar-dia. Electroencephalogram (EEG) showed a pathologicalbrain wave pattern with decreased brain activity. On day38 of life, a pale skin and apneas were noted, with ventricu-lar tachycardia. The girl died from cardiovascular arrest.

MethodsSerum transferrin isoelectrofocusing was performed as re-ported [12]. Mutation analysis of the PMM2 and ALG8genes was performed according to standard methods [1, 13].In CDG, enzyme analyses are not available for all types

of defects in the pathway. When enzymatic analysislacks, lipid-linked oligosaccharides (LLO) in fibroblasts

Fig. 1 a,b Patient 4 at the age of 10 months - floppy infant, with multiple dysmorphic features such as a prominent forehead, wide fontanelle,macroglossia, dysplastic ears, high palate, inverted nipples, short fingers and toes and a pale mottled skin, ì fat padsî on arms and thighs [11]

Fig. 2 a,b Patient 5 at the age of 20 days - floppy infant, with intermittent dystonic posturing, and multiple dysmorphic features such as anabnormal fat distribution on arms and thighs, macroglossia, low-set ears, additionally, cataracts and persisting primary vitreous artery were present

Hˆ ck et al. Orphanet Journal of Rare Diseases (2015) 10:73 Page 5 of 8

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Inherited Metabolic Diseases

Georg F. Hoff mannJohannes ZschockeWilliam L. NyhanEditors

123

A Clinical Approach

Second Edition

xiii

28 Metabolic M yopathies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Stephen G. Kahler

29 Psychiatric D isease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Ertan Mayatepek

30 Eye D isorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 Alberto Burlina , Andrea Celato , a nd Alessandro P. Burlina

31 Skin and Hair D isorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 Diego Martinelli , Maya El Hachem , Enrico Bertini , a nd Carlo Dionisi-Vici

32 The B one in Ge netic and M etabolic D iseases: A Practical Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 Andrea Superti-Furga , Luisa BonafÈ , a nd Sheila Unger

33 Physical A bnormalities i n M etabolic D iseases . . . . . . . . . . . . . . 381 Ute Moog , Johannes Zschocke , a nd Stephanie Gr¸ne wald

34 Hematological D isorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 Ellen Crushell a nd Joe T. R. Clarke

35 Immunological Pr oblems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411 Ertan Mayatepek

Part IV Investigations for Metabolic Diseases

36 Newborn S creening f or I nherited M etabolic D isease . . . . . . . . 421 Dietrich Matern a nd Piero Rinaldo

37 Biochemical Studie s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 Miao He a nd K. Michael Gibson

38 Enzyme D iagnostics i n a C hanging W orld of E xome Sequencing and Newborn Screening as Exemplified for Peroxisomal, Mitochondrial, and Lysosomal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Ronald J. A. Wanders , Ben J. H. M. Poorthuis , and Richard J. T. Rodenburg

39 Molecular Ge netic A nalyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489 Johannes Zschocke

40 Family I ssues, C arrier T ests and Pr enatal D iagnosis . . . . . . . . 499 Johannes Zschocke

41 Function T ests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505 Johannes Zschocke a nd Stefan Kˆl ker

42 Diagnostic W orkup o f P atients w ith M itochondrial D iseases . . 521 Shamima Rahman a nd Nicole I. Wolf

43 Pathology: B iopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537 JoseÆ ne Radke , Werner Stenzel , a nd Hans H. Goebel

Contents

2017

31 Skin and Hair D isorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 Diego Martinelli , Maya El Hachem , Enrico Bertini , a nd Carlo Dionisi-Vici

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DoençasHereditáriasdoMetabolismoManifestaçõescutâneas

Manifestações cutâneas

! A importância no diagnóstico clínico

A Dermatologia nas DHM

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Manifestações cutâneas

Frequentes (0->85%) Múltiplas e variadas Não específicas

DoençasHereditáriasdoMetabolismoManifestaçõescutâneas

Manifestações cutâneas

à nascença (hipopigmentação, bebé collodium) precoces (pili torti, angioqueratomas)

Tardias ! alterações irreversíveis

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Manifestações cutâneas

Mecanismos complexos

Acumulação de metabolito anormal

Ausência de metabolito essencial

Interferência em múltiplos passos metabólicos

....

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B

DoençasHereditáriasdoMetabolismoManifestaçõescutâneas

Manifestações cutâneas

Acumulação de metabolito anormal pigmentação fotosensibilidade alterações vasculares calcificação, placas/nódulos, ...

Ausência de produto essencial hipopigmentação pele e cabelos alterações epidérmicas – hiperqueratose/necrose epidérmica alterações fibras elásticas (cutis laxa) alterações do colagénio ... (reacções esclerodermiformes) alterações estruturais cabelos

… e “rash” cutâneo aplasia cutis Alt . sudação ...

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Hiperpigmentação Melanina Pigmentos anómalos (ocronose) Fe/Cu + melanina

Áreas foto-expostas Zonas fricção Mucosas Localizadas

DoençasHereditáriasdoMetabolismoManifestaçõescutâneas

D Addison ACTH MSH

Hemocromatose D Wilson D Gaucher

Patchtes?ng–alinkbetweenACDanddrugerup?ons

Doença de Wilson (Cu) Hiperpigmentação difusa

Face - pernas Lúnulas azuis Aneis Kayser-Fleischer Canície precoce à Tto D-penicilamina

Patchtes?ng–alinkbetweenACDanddrugerup?ons

Doença de Wilson (Cu) Hiperpigmentação difusa

Face - pernas Lúnulas azuis Aneis Kayser-Fleischer Canície precoce à Tto D-penicilamina à elastose perfurante serpiginosa

DoençasHereditáriasdoMetabolismoManifestaçõescutâneas

Alcaptonúria (homogentisic acid oxidase)

HGO cartilagens

tec conjuntivo Urina, suor

DoençasHereditáriasdoMetabolismoManifestaçõescutâneas

Alcaptonúria – OCRONOSE Pigmentação “Salt and pepper spots“

à confluente Pav auricular esclera nariz articulações

DoençasHereditáriasdoMetabolismoManifestaçõescutâneas

N Engl J Med, Vol. 347, No. 26

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ALKAPTONURIA

NATURAL HISTORY OF ALKAPTONURIA

C

HANIKA

P

HORNPHUTKUL

, M.D., W

ENDY

J. I

NTRONE

, M.D., M

ONIQUE

B. P

ERRY

, M.D., I

SA

B

ERNARDINI

, M.E

D

., M

ARK

D. M

URPHEY

, M.D., D

IANA

L. F

ITZPATRICK

, B.A., P

AUL

D. A

NDERSON

, B.A., M

ARJAN

H

UIZING

, P

H

.D., Y

AIR

A

NIKSTER

, M.D., L

YNN

H. G

ERBER

, M.D.,

AND

W

ILLIAM

A. G

AHL

, M.D., P

H

.D.

A

BSTRACT

Background

Alkaptonuria, caused by mutationsin the

HGO

gene and a deficiency of homogentisate1,2-dioxygenase, results in an accumulation of ho-mogentisic acid (HGA), ochronosis, and destructionof connective tissue. There is no effective therapy forthis disorder, although nitisinone inhibits the enzymethat produces HGA. We performed a study to delin-eate the natural history of alkaptonuria.

Methods

We evaluated 58 patients with alkaptonuria(age range, 4 to 80 years), using clinical, radiographic,biochemical, and molecular methods. A radiographicscoring system was devised to assess the severity ofspinal and joint damage. Two patients were treatedwith nitisinone for 10 and 9 days, respectively.

Results

Life-table analyses showed that joint re-placement was performed at a mean age of 55 yearsand that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary-artery cal-cification at 59 years. Linear regression analysis indi-cated that the radiographic score for the severity ofdisease began increasing after the age of 30 years,with a more rapid increase in men than in women.Twenty-three new

HGO

mutations were identified. Ina 51-year-old woman, urinary HGA excretion fell from2.9 to 0.13 g per day after a 10-day course of nitisinone(7 days at a dose of 0.7 mg per day and 3 days at 2.8mg per day). In a 59-year-old woman, urinary HGA fellfrom 6.4 g to 1.7 g per day after nine days of treatmentwith nitisinone (0.7 mg per day). Plasma tyrosine lev-els in these patients rose from approximately 1.1 mgper deciliter (60 µmol per liter) in both to approximate-ly 12.8 mg per deciliter (700 µmol per liter) and 23.6mg per deciliter (1300 µmol per liter), respectively,with no clinical signs or symptoms.

Conclusions

The reported data on the natural histo-ry of alkaptonuria provide a basis for the evaluationof long-term therapies. Although nitisinone can re-duce HGA production in humans with homogentisate1,2-dioxygenase deficiency, the long-term safety andefficacy of this treatment require further evaluation.(N Engl J Med 2002;347:2111-21.)

Copyright © 2002 Massachusetts Medical Society.

From the Section on Human Biochemical Genetics, Heritable DisordersBranch, National Institute of Child Health and Human Development, Be-thesda, Md. (C.P., W.J.I., I.B., D.L.F., P.D.A., M.H., Y.A., W.A.G.); theRehabilitation Medicine Department, National Institutes of Health ClinicalCenter, Bethesda, Md. (M.B.P., L.H.G.); the Department of RadiologicPathology, Armed Forces Institute of Pathology, Washington, D.C.; theDepartment of Radiology, University of Maryland Medical Center, Baltimore;and the Departments of Radiology and Nuclear Medicine, Uniformed Serv-ices University of the Health Sciences, Bethesda, Md. (M.D.M.). Addressreprint requests to Dr. Gahl at 10 Center Dr., MSC 1851, Bldg. 10, Rm.10C-103, Medical Genetics Branch, National Human Genome ResearchInstitute, National Institutes of Health, Bethesda, MD 20892-1851, or atbgahl@helix.nih.gov.

HIS year marks the 100th anniversary of SirArchibald Garrod’s description of alkapto-nuria (Mendelian Inheritance in Man num-ber 203500) as the first disorder in humans

to be found to conform to the principles of mendelianautosomal recessive inheritance.

1

In his Croonian lec-tures of 1908,

2

Garrod coined the term “inborn errorof metabolism” and proposed that alkaptonuria resultsfrom a deficiency of an enzyme that normally splits thearomatic ring of homogentisic acid (HGA) (Fig. 1), atyrosine-degradation product known to accumulate inpatients with alkaptonuria.

3

Indeed, alkaptonuria is as-sociated with deficient homogentisate 1,2-dioxygen-ase (HGO) activity in the liver,

4

and the gene for HGOis mutated in patients with alkaptonuria.

5

HGO de-ficiency causes excretion of large quantities of HGAdaily in the urine,

6,7

which turns dark on standing. Inurine, as in tissues, HGA oxidizes to benzoquinones,which in turn form melanin-like polymers. Accumu-lation of HGA and its metabolites in tissues causesochronosis, with darkening of cartilaginous tissues andbone, arthritis and joint destruction, and deteriorationof cardiac valves.

3,6,7

Treatment with vitamin C to en-hance HGA degradation has not proved helpful.

3,8

However, 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, or nitisinone (Orfadin), has beenproposed as potential therapy

9

because it inhibits theenzyme that produces HGA (i.e., 4-hydroxyphenyl-pyruvate dioxygenase) (Fig. 1).

10

We performed aclinical, biochemical, and molecular evaluation of 58patients with alkaptonuria.

METHODS

Patients

Sixty-four patients (33 male and 31 female; age range, 4 to 80years) from 54 different families were enrolled in the study. The pro-tocol was approved by the institutional review board of the NationalInstitute of Child Health and Human Development, and all patients

T

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www.nejm.org

The New England Journal of Medicine

a 51-year-old woman who was a compound hetero-zygote for the W97R and F136Y mutations, received0.35 mg of nitisinone twice a day for seven days. Theurinary HGA level decreased from approximately 2.9to 0.9 g per day (Fig. 6A). The dose was increasedto 1.4 mg twice a day for three days, after which theurinary HGA level fell to 0.13 g per day and the uri-nary hydroxyphenylpyruvate level became very elevat-ed. The plasma tyrosine level rose from approximately1.1 mg per deciliter (60 µmol per liter) to 12.6 mg perdeciliter (697 µmol per liter) on day 7 and to 13.0 mgper deciliter (719 µmol per liter) on day 10. At thattime, laboratory tests performed on day 7, showing anelevated plasma tyrosine level, became available, andthe treatment was stopped. There were no symptomsof photophobia, and a slit-lamp examination of thecorneas showed no abnormalities. The plasma tyro-sine level fell to 2.5 mg per deciliter (140 µmol perliter), and the urinary HGA level increased to 3.0 g perday over the next 14 days (Fig. 6A).

The other patient, a 59-year-old woman who was acompound heterozygote for the G161R and S305Fmutations, received 0.35 mg of nitisinone twice a dayfor nine days. Her urinary HGA level fell from 6.4 gper day on day 0 to 1.7 g per day on day 9 (Fig. 6B).

The plasma tyrosine level rose from 1.2 mg per dec-iliter (67 µmol per liter) to 20.8 mg per deciliter (1147µmol per liter) on day 8 and to 23.3 mg per deciliter(1288 µmol per liter) on day 9. At that time, labo-ratory tests performed on day 6, showing an elevatedplasma tyrosine level, became available, and the treat-ment was stopped. The plasma tyrosine level fell to2.5 mg per deciliter (137 µmol per liter) over the next25 days. The patient remained asymptomatic.

DISCUSSION

The Egyptian mummy Harwa, dating from 1500

B

.

C

., had alkaptonuria,

23

but the term “alcapton” wasfirst used in 1859 to describe a patient’s urinary re-ducing compound,

24

later identified as 2,5-dihydroxy-phenylacetic acid, or homogentisic acid.

25

By 1908,Garrod had proposed that alkaptonuria was an inbornerror of metabolism,

2

and by 1909, Neubauer hadmapped the complete tyrosine-degradation pathway.

26

A review of cases of alkaptonuria throughout theworld noted that approximately 600 cases had beendescribed through 1962.

7

We estimate that the cur-rent incidence of alkaptonuria is 1 case in 250,000 to1 million live births.

Clinically, alkaptonuria resembles ankylosing spon-

Figure 3.

Ochronotic Pigmentation of Sclerae and Ear Cartilage at Various Ages.These are examples of the most extensive involvement for each age group.

31–40 Yr 41–50 Yr 51–60 Yr 61–80 Yr

The New England Journal of Medicine Downloaded from nejm.org on December 5, 2016. For personal use only. No other uses without permission.

Copyright © 2002 Massachusetts Medical Society. All rights reserved.

Ø  30 anos

Ø  Dign precoce?

Ø  Não específica

Alcaptonúria OCRONOSE

� � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � Ma� � � � M� � f a � � � M� �

� � � � � � � � �� � � � � � � � � �

Hipopigmentação melânica

Pele clara e cabelos “palha” Olhos azulados, nistagmo, fotofobia

Fenilcetonúria (< tirosina, substrato para sintese melanina) Doença de Menkes (Cu – cofator tirosinase àsintese melanina) Homocistinúria Chediak-Higashi (albinismo parcial) Hermansky-Pudlack (plaquetas) Formação /transporte/exocitose Griscelli-Prunières melanosomas Doenças da glicosilação

DoençasHereditáriasdoMetabolismoManifestaçõescutâneas

Fenilcetonúria Diagnóstico e tratamento precoce

� � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � Ma� � � � M� � f a � � � M� �

� � � � � � � � �n� � e� � � � �

Angioqueratomas Angioqueratoma corporis diffusum

Telangiectasias Angiomas Acrocianose

A Livedo reticularis / D Raynaud Cutis marmorata congénita Úlceras de perna (def prolidase)

� � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � Ma� � � � M� � f a � � � M� �

Doença de Fabry Angioqueratoma corporis diffusum Enzima lisosomal α galactosidade A é  glicoesfingolipidos (cel endoteliais, … X-linked recessive à Males >> females

Início médio 14-16 anos; presentes em 66% Masc/36% fem

1254 www.thelancet.com Vol 378 October 1, 2011

Clinical Picture

Lancet 2011; 378: 1254

Published OnlineJuly 29, 2011

DOI:10.1016/S0140­6736(11)60473­ X

Department of Dermatology (G Sethuraman MD,

Kavish Chouhan MD, Prof V K Sharma MD) and

Department of Pathology (S Kaushal MD), All India

Institute of Medical Sciences, New Delhi, India

Correspondence to:Dr Gomathy Sethuraman,

Department of Dermatology, All India Institute of Medical Sciences,

New Delhi 110029, Indiakgsethu@yahoo.com

Fabryí s diseaseGomathy Sethuraman, Kavish Chouhan, Seema Kaushal, Vinod K Sharma

A 17­yea r­o ld boy had hypohydrosis since early childhood; generalised telangiectasias including the palms, soles, and mucosae for the past 7 years (fi gure A–C ); and paraesthesia of his fi ngers and toes for the past 4 years. He was of short stature and had delayed puberty. His maternal uncle had hypohidrosis and pain of his hands and feet, and died of a cardiovascular event before the age of 40 years. Urine analysis showed occasional maltese cross globules on polarising microscopy (fi gure D). Skin biopsy was consistent with angiokeratoma (fi gure E). α­g alactosidase A enzyme activity was low. Nerve

conduction studies showed small fi bre neuropathy. His bone age was 8∙42–1 3∙05 years. Dual­emi ssion x­ ray absorptiometry scan showed osteoporosis (Z score –4) . Thyroid profi le and testosterone concen trations were normal. Cardiac and pulmonary function tests and ophthalmological evaluations were normal. His blood group was B+. MRI brain and ultrasonography of the abdomen were also normal. A diagnosis of Fabry’s disease (angiokeratoma corporis diff usum) was made. Fabry’s disease is a rare X­li nked lysomal storage disorder resulting from a defi ciency of α­g alactosidase A.

Figure: Presentation of Fabryí s disease(Añ C) Telangiectasias; (D) urine analysis showing birefringent lipid molecules; and (E) skin biopsy showing angiokeratoma (haematoxylin and eosin stain).

A B

D E

C

100 µm

� � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � Ma� � � � M� � f a � � � M� �

images in clinical medicine

The

new england journal

of

medicine

n engl j med

349;21

www.nejm.org november

20, 2003

e

20

Fabry’s Disease

Jeffrey B. Kopp, M.D.Raphael Schiffmann, M.D.

National Institutes of HealthBethesda, MD 20892

A B

C

D

30-year-old man had severe neuropathic pain that affected

his hands and feet. Examination of his skin showed angiokeratomas that wereparticularly prominent in the groin and on the back (Panel A) but that were

also present on the lips and palms. Examination of the optic fundi showed tortuousretinal arterioles (Panel B). He had heat intolerance and decreased sweating. The diag-nosis of Fabry’s disease was confirmed by the detection of reduced

a

-galactosidase Aactivity in peripheral leukocytes. He received carbamazepine for the neuropathic pain.Testing of renal function when the patient was 38 years of age showed a serum creati-nine concentration of 1.1 mg per deciliter (97.2 µmol per liter), a creatinine clearancerate of 92 ml per minute per 1.73 m

2

of body-surface area, and a protein excretion rateof 3.9 g per day. Renal biopsy showed an accumulation of toluidine blue staining in cel-lular inclusions that was prominent in glomerular podocytes and also present in distaltubular epithelial cells and extraglomerular vascular cells (Panel C, ¬80). Electron-microscopical examination of the glomerulus revealed podocytes bearing electron-dense lamellar bodies that represented secondary lysosomes containing glycolipid(Panel D, ¬3800). The patient is being treated with

a

-galactosidase A administered byintravenous infusion every two weeks. His symptoms have improved, although his renalfunction has continued to deteriorate, with a serum creatinine concentration now of2.2 mg per deciliter (194.5 µmol per liter).

Copyright © 2003 Massachusetts Medical Society.

a

The New England Journal of Medicine Downloaded from nejm.org on December 5, 2016. For personal use only. No other uses without permission.

Copyright © 2003 Massachusetts Medical Society. All rights reserved.

1254 www.thelancet.com Vol 378 October 1, 2011

Clinical Picture

Lancet 2011; 378: 1254

Published OnlineJuly 29, 2011

DOI:10.1016/S0140­6736(11)60473­ X

Department of Dermatology (G Sethuraman MD,

Kavish Chouhan MD, Prof V K Sharma MD) and

Department of Pathology (S Kaushal MD), All India

Institute of Medical Sciences, New Delhi, India

Correspondence to:Dr Gomathy Sethuraman,

Department of Dermatology, All India Institute of Medical Sciences,

New Delhi 110029, Indiakgsethu@yahoo.com

Fabryí s diseaseGomathy Sethuraman, Kavish Chouhan, Seema Kaushal, Vinod K Sharma

A 17­yea r­o ld boy had hypohydrosis since early childhood; generalised telangiectasias including the palms, soles, and mucosae for the past 7 years (fi gure A–C ); and paraesthesia of his fi ngers and toes for the past 4 years. He was of short stature and had delayed puberty. His maternal uncle had hypohidrosis and pain of his hands and feet, and died of a cardiovascular event before the age of 40 years. Urine analysis showed occasional maltese cross globules on polarising microscopy (fi gure D). Skin biopsy was consistent with angiokeratoma (fi gure E). α­g alactosidase A enzyme activity was low. Nerve

conduction studies showed small fi bre neuropathy. His bone age was 8∙42–1 3∙05 years. Dual­emi ssion x­ ray absorptiometry scan showed osteoporosis (Z score –4) . Thyroid profi le and testosterone concen trations were normal. Cardiac and pulmonary function tests and ophthalmological evaluations were normal. His blood group was B+. MRI brain and ultrasonography of the abdomen were also normal. A diagnosis of Fabry’s disease (angiokeratoma corporis diff usum) was made. Fabry’s disease is a rare X­li nked lysomal storage disorder resulting from a defi ciency of α­g alactosidase A.

Figure: Presentation of Fabryí s disease(Añ C) Telangiectasias; (D) urine analysis showing birefringent lipid molecules; and (E) skin biopsy showing angiokeratoma (haematoxylin and eosin stain).

A B

D E

C

100 µm

Lancet 2011; 378: 1254

Dores lancinantes mãos e pés ê sudação e febre à rim/coração/SNC

95%/88% Cornea verticilata

Telangiectasias

� � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � Ma� � � � M� � f a � � � M� �

344

present skin manifestations that can be grouped into hair abnormalities, rashes, pigmentation abnormalities, and acrocyanosis: moreover, a growing number of skin disorders present with secondary mitochondrial pathology. Different molecular defects can cause dysfunctional mito-chondria, including mutations in mitochondrial- and nuclear DNA-encoded subunits and assembly factors of oxidative phosphorylation (OXPHOS) complexes, mutations in intermediate Æ lament proteins involved in mitochondria dynamics, dis-orders of mitochondrial DNA metabolism, fatty acid metabolism and heme synthesis, and disor-ders of mtDNA repair (Feichtinger et al. 2014 ).

We will describe these disorders separately in the different subchapters according to the pri-mary skin manifestation.

Acrocyanosis appears as a bilateral mottled discoloration of the entire feet or hands. In rela-tion to a vasospasm of small arterioles and venules with secondary dilatation of capillaries, the skin' s color becomes bright red, with no tro-phic changes and pain. Orthostatic acrocyanosis is one of the principal signs of ethylmalonic encephalopathy, a devastating mitochondrial dis-order affecting the brain, gastrointestinal tract, and peripheral vessels (Fig. 31.1 ).

Remember

Orthostatic acrocyanosis is a key sign of ethyl-malonic e ncephalopathy.

Acrocyanosis may also be observed in other mitochondrial disorders with onset in early infancy and multisystem involvement (Bodemer et al. 1999 ). Acrocyanosis and livedo reticularis may be observed in hyperoxaluria type I along with urolithiasis, nephrocalcinosis, renal failure, peripheral vascular insufÆ ciency, arterial occlu-sion, and Raynaud phenomenon.

Capillary malformations appearing as light pink to deep-red angiomas or as telangiectasia may occur in several metabolic diseases. Widespread hemangiomas, coarse facies, con-junctival telangiectasia, severe developmental delay, seizures, and skeletal abnormalities can be observed in neuraminidase deÆ ciency. Facial capillary hemangioma, severe photosensitivity, eczema, and blond hair are typical features of the Smith±Le mli±O pitz syndrome, a disorder of cholesterol biosynthesis presenting with charac-teristic facial appearance, ambiguous genitalia, failure to thrive, syndactyly, microcephaly, and intellectual impairment (see also paragraph on photosensitivity). In transaldolase deÆ ciency, a metabolic disease of pentose phosphate pathway reported in patients with liver failure and cirrho-sis; dysmorphic facial features; renal, cardiac, and hematological involvement; and cutaneous signs include telangiectasia, cutis laxa, and hypertrichosis (Valayannopoulos et al. 2006 ). More rarely, vascular signs have been observed in patients with congenital disorder of glycosyl-ation (CDG) along with neurologic, facial, and other multisystem abnormalities. These include DPM1-CDG (CDG type Ie), MGAT2-CDG (CDG type IIa), and SLC35A1-CDG (CDG type IIf) (Dyer et al. 2005 ).

Prolidase deÆ ciency, which also presents with diffuse telangiectasia, will be discussed in the skin eruption paragraph.

Visible veins are frequently observed in two other disorders of proline metabolism, pyrroline- 5- carboxylate synthetase and pyrroline-5- carboxylate reductase 1 deÆ ciencies, which will be discussed in the skin laxity paragraph.

Fig. 31.1 Orthostatic acrocyanosis in ethylmalonic encephalopathy

D. Martinelli et al.