Mitry, Mira, MD

Ross, James, MD, FACP

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Lehigh Valley Health NetworkLVHN Scholarly WorksDepartment of MedicineInborn Error of Metabolism is a Disease of any Age;Carniting Palmitoyltransferase II Deficiency and ItsManifestationsMira Mitry MDLehigh Valley Health Network, Mira.Mitry@lvhn.orgJames Ross MD, FACPLehigh Valley Health Network, James.Ross@lvhn.orgFollow this and additional works at: http://scholarlyworks.lvhn.org/medicinePart of the Medical Sciences Commons, Nutritional and Metabolic Diseases Commons, and theRheumatology CommonsThis Poster is brought to you for free and open access by LVHN Scholarly Works. It has been accepted for inclusion in LVHN Scholarly Works by anauthorized administrator. For more information, please contact LibraryServices@lvhn.org.Published In/Presented AtMitry, M., & Ross, J. (April 29, 2014). Inborn Error of Metabolism is a Disease of any Age; Carniting Palmitoyltransferase II Deficiency andits Manifestations. Poster presented at: LVHN Research Day, Allentown, PA.Lehigh Valley Health Network, Allentown, PennsylvaniaInborn Error of Metabolism is a Disease of any Age; Carniting Palmitoyltransferase II Deficiency and Its ManifestationsMira Mitry, MD, James Ross MD, FACPReferences:1.	 	Longo	N,	Amat	di	San	Filippo	C,	Pasquali	M.	Disorders	of	carnitine	transport	and	the	carnitine	cycle.	Am	J	Med	Genet	C	Semin	med	Genet.	2006	May	2006	15;142C	(2):	77-85.2.	 	Monograph.	L-carnitine.Altern	Med	Rev.	2005	Mar;10(1):42-50.	(seizure).	3.	 	Corti	S	et	al.	(2008).	Clinical	features	and	new	molecular	findings	in	Carnitine	Palmitoyltransferase	II	(CPT	II)	deficiency.	J	Neurol	Sci,	266(1-2):	97-103.	(autosome	inheriance).4.	 	Tanphaichitr	V,	Leelahagul	P.	Carnitine	metabolism	and	human	carnitine	deficiency.	Nutrition.	1993	May-Jun;9(3):246-54.	(diagnosis).5.	 	Bonnefont	JP,	et	al.	Bezafibrate	for	an	inborn	mitochondrial	beta-oxidation	defect.	N	Engl	J	Med.	2009	Feb	19;360(8):838-40.6.	 	Kilfoyle	D,	Hutchinson	D,	Potter	H,	George	P.	Recurrent	myoglobinuria	due	to	carnitine	palmitoyltransferase	II	deficiency:	clinical,	biochemical,	and	genetic	features	of	adult-onset	cases.	N	Z	med	J	2005;	118:U1320.7.	 	Orngreen	MC,	Eistrup	R,	Vissing	J.	Effect	of	diet	on	exercise	tolerance	in	carnitine	palmitoyltransferase	II	deficiency.	Neurology	2003;	61:559.8.	 	Roe	CR,	Yang	BZ,	Brunengraber	H,	et	al.	Carnitine	palmitoyltransferase	II	deficiency:	successful	anaplerotic	diet	therapy.	Neurology	2008;	71:260.9.	 	The	Mitochondrial	Carnitine	System.	Linus	Palding	Institute	at	Oregon	State	University.	http://lpi.oregonstate.edu/infocenter/othernuts/carnitine/transport.html.	Accessed	April	25,	2014.© 2014 Lehigh Valley Health NetworkIntroduction:•	 	Carnitine	palmitoyltransferase	II	(CPT	II)	deficiency	is	a	disorder	of	long-chain	fatty-acid	oxidation.	The	three	clinical	presentations	are:	lethal	neonatal	form,	severe	infantile	hepatocardiomuscular	form,	and	myopathic	form.	Chief Complaint:	“Pain	in	my	thighs”.Carnitine Palmitoyltransferase II:•	 	Carnitine	palmitoyl	transferase	II		(CPT	II),	is	an	enzyme	located	in	the	inner	aspect	of	the	inner	mitochondrial	membrane,	that	cleaves	the	long	chain	acylcarnitine	complex.	Subsequently,	long	chain	fatty	acid	could	be	used	in	beta	oxidation,	and	production	of	energy	in	the	liver,	cardiac	muscle	and	skeletal	muscle.	•	 	During	periods	of	fasting,	or	prolong	exercise;	if	fatty	acid	oxidation	is	defective,	fat	can’t	be	utilized,	and	glucose	is	consumed	without	regeneration	via	gluconeogenesis.	Eventually	hypoglycemia	occurs	leading	to	brain	function	impairment,	seizures	and	loss	of	consciousness.•	 	Moreover,	fat	will	accumulate	in	the	liver	causing	steatosis,	heart	causing	cardiomyopathy	and	arrhythmias,	and	skeletal	muscle	causing	myopathy.		Figure 1. The Mitochondrial Carnitine System. Linus Palding Institute at Oregon State University. http://lpi.oregonstate.edu/infocenter/othernuts/carnitine/transport.html. Accessed April 24, 2014.Case:•	 	30	years	old	female	with	PMH	of	migraine	and	seizures,	presented	with	severe	pain	in	her	thighs.	According	to	the	patient,	she	went	to	the	gym	2	days	prior	to	admission,	to	do	her	usual	workout,	which	consists	of	an	hour	of	running	or	aerobic	exercise.	However,	a	personal	trainer	offered	her	a	tense	15-minutes	workout	that	consisted	of	significant	amount	of	squats.	•	 	Later	that	day,	she	noticed	tightness,	and	muscle	stiffness	in	her	thighs,	which	became	progressively	worse	to	the	point	she	could	not	stand	or	walk.	She	also	noticed	that	her	urine	was	getting	dark	red/black	in	color.	Going Back Into Her History:•	 	Per	patient,	she	would	awake	every	morning	as	a	child	with	numbness	in	her	legs,	which	would	resolve	eventually	with	standing.	By	the	time	she	was	17,	she	began	having	episodes	associated	with	muscle	pain,	weakness,	and	fatigue	with	exercise.	If	her	muscles’	pain	is	severe	enough,	she	would	develop	a	seizure	like	activity,	followed	by	a	transient	loss	of	consciousness.	There	is	no	postictal	state.	•	 	Less	severe	more	frequent	pain	during	her	daily	activity	without	definite	exercise.Past Medical History: Questionable	seizures;	her	EEG	was	abnormal	but	nonspecific.	Migraine,	polycystic	ovarian	disease	and	fibromyalgia.Medications: Topamax,	Aldactone,	OCP.	Family History: Brother	has	myalgia	and	darkening	of	urine	after	exercise	but	it	was	never	worked	up.	Sister	had	2	episodes	of	passing	out,	but	no	workup	was	done.	Cousin	with	epilepsy.	Vitals: Temp	=	97.9,	HR	=	85,	Bp	=	117/74,	RR	=	20,	and	SpO2	=	93%	on	RA.General: AAOx3,	no	apparent	distress.	Physical Examination: Physical	examin	is	pertinent	for;	bilateral	lower	extremities	were	extremely	painful	and	tender	on	palpation.	Tense	bilateral	thighs	and	quadriceps.	Pain	on	pasive	motion	with	rigidity	of	b/l	knees.	Sensory	exam	was	intact	to	pinprick	throughout	with	subjective	decrease	in	the	left	medial	calf	region.	The	rest	of	the	physican	exam	was	negative.Labs and Imaging: CBC,	Hgb	of	14.9,	Hematocrit	44.8,	WBC	14	and	platelets	311.	BMP	was	within	normal	range.	Ca	9.1,	AST	1529,	ALT	452,	CK	is	108,864.	Acetaminophen	is	<10.	UA	was	positive	for	blood,	but	rare	RBC	on	HPF,	moblobin	test	was	positive.	EKG	-	normal	sinus	rhythm.Hospital Course: 	Patient	was	started	on	aggressive	fluid	resuscitation	for	rhabdomyolysis.	Orthopedics	were	consulted	for	possible	compartment	syndrome.	Thighs’	anterior	compartment	pressure	was	measured,	and	it	was	found	to	be	55-60	on	the	right	and	90	on	the	left.	Patient	was	taken	for	stat	fasciotomy.		During	which,	all	her	muscles	appeared	healthy,	clean,	viable	and	contractile.		Also	Rheumatology	was	consulted	and	recommendation	was	to	do	muscle	biopsy	during	fasciotomy.	Muscle	biopsy	was	done	on	closure	of	the	fasciotomy	and	was	sent	for	pathology.	Pathology	reading,	necrotizing	myopathy	with	excessive	lipis	storage.Diagnosis: Deficiency	of	Carnitine	palmitoyltransferase	II.The Myopathic Form of CPT II:•	 	The	myopathic	form	of	CPT	II	deficiency	is	the	most	common	disorder	of	lipid	metabolism	affecting	skeletal	muscle,	and	the	most	frequent	cause	of	hereditary	myoglobinuria.•	 	Signs/Symptoms	  –  Usually	noted	during	first	or	second	decade	of	life,	but	can	appear	as	late	as	the	fifth	decade.	  –  Characterized	by	attacks	of	myalgia,	muscle	stiffness	or	tenderness,	weakness,	and	fatigue,	with	or	without	myoglobinuria.	Lethargy	and	seizures	can	happen.		  –  When	rhabdomyolysis	occurs,	it	may	lead	to	acute	renal	failure,	electrolytes	abnormality	causing	cardiac	arrhythmias,	and	respiratory	insufficiency	requiring	mechanical	ventilation.•	 	Triggers:	  –  Prolonged	exercise  –  Cold	exposure  –  Fever  –  Stress	or	infection  –  Medications	that	may	lower	carnitine	levels,	like	pentobarbital,	phenytoin,	carbamazepine,	depakote,	sulfadiazine,	pyrimethamine,	cefditoren,	ipecac,	and	zidovudine.	•	 	Diagnosis	  –  Determination	of	free	and	acylcarnitine	levels	in	serum,	urine	and/tissues.  –  Confirmation	by	direct	enzymatic	assay	or	DNA	analysis.	•	 	Treatments;	no	specific	treatment	exists.	Preventive	measures	include;  –  Diet	modification;	high	carbohydrate,	low	(medium-chain)	fat	and	low	protien	diet.	Frequent	meals.	Extra	carbohydrate	intake	before	sustained	exercise	appears	to	improve	exercise	intolerance.  –  Triheptanoin	diet	appears	promising.	Larger	studies	are	needed	to	confirm.  –  Refrain	from	prolonged	aerobic	exercise,	fasting	and	cold	exposure.  –  Pharmacologic	treatment	with	bezafibrate	may	be	beneficial	for	mild	CPT	II	deficiency.	Larger	studies	are	needed	to	confirm.	Figure 2. CPT II Deficiency.The carnitine cycle in fatty acid oxidation. In: Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. American Journal Of Medical Genetics. Part C, Seminars In Medical Genetics. May 15, 2006;142C(2):77-85.Carnitine Palmitoyltransferase II Deficiency:•	 	It	has	an	autosomal	recessive	pattern	of	inheritance.	•	 	A	majority	of	affected	individuals	are	homozygous	or	compound	heterozygotes	for	mutations	in	the	CPT	II	gene.•	 	The	two	most	common	gene	defects,	S113L	and	R503C	may	cause	disease	in	heterozygotes.•	 	The	three	clinical	presentations	are:	lethal	neonatal	form,	severe	infantile	hepatocardiomuscular	form,	and	myopathic	form.	The	former	2	presentations	are	fatal	at	young	age.Teaching Point:•	 	Internists	need	to	be	aware	of	the	manifestations	of	inborn	error	of	muscle	metabolism	which	can	also	present	in	adults.	This	case	was	diagnosed	14	years	after	her	initial	presentation	and	after	been	evaluated	by	22	specialists.	

Inborn Error of Metabolism is a Disease of any Age; Carniting Palmitoyltransferase II Deficiency and Its Manifestations

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Inborn Error of Metabolism is a Disease of any Age; Carniting Palmitoyltransferase II Deficiency and Its Manifestations

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