manu/mldr-zoomed-100char-total-queries-documents

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128_202	See also Cowper and Newton Museum References Notes Citations Sources
128_203	. Preface by Haweis
128_204	(More legible (and machine-readable) transcription. For the facsimile edition at archive.org, see
128_205	below.)
128_206	Further reading
128_207	External links
128_208	Newton, John (1788). Thoughts Upon the African Slave Trade (Internet Archive with funding by
128_209	Associates of the Boston Public Library ed.). London: J. Buckland & J. Johnson. Retrieved 24 May
128_210	2019. (Facsimile of original book at Archive.org. For more legible (and machine-readable)
128_211	transcription, see Sources (above).)
128_212	The John Newton Project Biography & Articles on Newton
128_213	John Newton Papers Collection from the Digital Library of Georgia John Newton on Poeticous
128_214	1725 births 1807 deaths 18th-century English Anglican priests 18th-century Royal Navy personnel
128_215	19th-century English people English slave traders Calvinist and Reformed hymnwriters
128_216	Christian abolitionists Church of England hymnwriters Doctors of Divinity English abolitionists
128_217	English evangelicals Evangelical Anglicans Evangelical Anglican clergy
128_218	Evangelicalism in the Church of England People from Aveley People from Wapping Royal Navy officers
128_219	Royal Navy sailors Sailors from London
129_0	Glycogen storage disease type II, also called Pompe disease, is an autosomal recessive metabolic
129_1	disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation
129_2	of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. It is
129_3	the only glycogen storage disease with a defect in lysosomal metabolism, and the first glycogen
129_4	storage disease to be identified, in 1932 by the Dutch pathologist J. C. Pompe.
129_5	The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and
129_6	affects various body tissues, particularly in the heart, skeletal muscles, liver and the nervous
129_7	system.
129_8	Signs and symptoms Newborn
129_9	The infantile form usually comes to medical attention within the first few months of life. The
129_10	usual presenting features are cardiomegaly (92%), hypotonia (88%), cardiomyopathy (88%),
129_11	respiratory distress (78%), muscle weakness (63%), feeding difficulties (57%) and failure to thrive
129_12	(50%).
129_13	The main clinical findings include floppy baby appearance, delayed motor milestones and feeding
129_14	difficulties. Moderate hepatomegaly may or may not be present. Facial features include
129_15	macroglossia, wide open mouth, wide open eyes, nasal flaring (due to respiratory distress), and
129_16	poor facial muscle tone. Cardiopulmonary involvement is manifested by increased respiratory rate,
129_17	use of accessory muscles for respiration, recurrent chest infections, decreased air entry in the
129_18	left lower zone (due to cardiomegaly), arrhythmias and evidence of heart failure.
129_19	Prior to the development of a treatment, median age at death in untreated cases was 8.7 months,
129_20	usually due to cardiorespiratory failure, however this outcome is drastically changed since
129_21	treatment has been available, improving with early access to treatment.
129_22	Late onset form
129_23	This form differs from the infantile principally in the relative lack of cardiac involvement. The
129_24	onset is more insidious and has a slower progression. Cardiac involvement may occur but is milder
129_25	than in the infantile form. Skeletal involvement is more prominent with a predilection for the
129_26	lower limbs.
129_27	Late onset features include impaired cough, recurrent chest infections, hypotonia, progressive
129_28	muscle weakness, delayed motor milestones, difficulty swallowing or chewing and reduced vital
129_29	capacity.
129_30	Prognosis depends on the age of onset of symptoms with a better prognosis being associated with
129_31	later onset disease.
129_32	Cause
129_33	It has an autosomal recessive inheritance pattern. This means the defective gene is located on an
129_34	autosome, and two faulty copies of the gene — one from each parent — are required to be born with
129_35	the disorder. As with all cases of autosomal recessive inheritance, children have a 1 in 4 chance
129_36	of inheriting the disorder when both parents carry the defective gene, and although both parents
129_37	carry one copy of the defective gene, they are usually not affected by the disorder.
129_38	The disease is caused by a mutation in a gene (acid alpha-glucosidase: also known as acid maltase)
129_39	on long arm of chromosome 17 at 17q25.2-q25.3 (base pair 75,689,876 to 75,708,272). The number of
129_40	mutations described is currently (in 2010) 289 with 67 being non-pathogenic mutations and 197
129_41	pathogenic mutations. The remainder are still being evaluated for their association with disease.
129_42	The gene spans approximately 20 kb and contains 20 exons with the first exon being noncoding. The
129_43	coding sequence of the putative catalytic site domain is interrupted in the middle by an intron of
129_44	101 bp. The promoter has features characteristic of a 'housekeeping' gene. The GC content is high
129_45	(80%) and distinct TATA and CCAAT motifs are lacking.
129_46	Most cases appear to be due to three mutations. A transversion (T → G) mutation is the most common
129_47	among adults with this disorder. This mutation interrupts a site of RNA splicing.
129_48	The gene encodes a protein—acid alpha-glucosidase (EC 3.2.1.20)—which is a lysosomal hydrolase. The
129_49	protein is an enzyme that normally degrades the alpha -1,4 and alpha -1,6 linkages in glycogen,
129_50	maltose and isomaltose and is required for the degradation of 1–3% of cellular glycogen. The
129_51	deficiency of this enzyme results in the accumulation of structurally normal glycogen in lysosomes
129_52	and cytoplasm in affected individuals. Excessive glycogen storage within lysosomes may interrupt
129_53	normal functioning of other organelles and lead to cellular injury.
129_54	A putative homologue—acid alpha-glucosidase-related gene 1—has been identified in the nematode
129_55	Caenorhabditis elegans.
129_56	Diagnosis
129_57	In the early-onset form, an infant will present with poor feeding causing failure to thrive, or
129_58	with difficulty breathing. The usual initial investigations include chest X ray, electrocardiogram
129_59	and echocardiography. Typical findings are those of an enlarged heart with non specific conduction
129_60	defects. Biochemical investigations include serum creatine kinase (typically increased 10 fold)
129_61	with lesser elevations of the serum aldolase, aspartate transaminase, alanine transaminase and
129_62	lactic dehydrogenase. Diagnosis is made by estimating the acid alpha glucosidase activity in either
129_63	skin biopsy (fibroblasts), muscle biopsy (muscle cells) or in white blood cells. The choice of
129_64	sample depends on the facilities available at the diagnostic laboratory.
129_65	In the late-onset form, an adult will present with gradually progressive arm and leg weakness, with
129_66	worsening respiratory function. Electromyography may be used initially to distinguish Pompe from
129_67	other causes of limb weakness. The findings on biochemical tests are similar to those of the
129_68	infantile form, with the caveat that the creatine kinase may be normal in some cases. The diagnosis
129_69	is by estimation of the enzyme activity in a suitable sample.
129_70	On May 17, 2013 the Secretary's Discretionary Advisory Committee on Heritable Diseases in Newborns
129_71	and Children (DACHDNC) approved a recommendation to the Secretary of Health and Human Services to
129_72	add Pompe to the Recommended Uniform Screening Panel (RUSP). The HHS secretary must first approve
129_73	the recommendation before the disease is formally added to the panel.
129_74	Classification
129_75	There are exceptions, but levels of alpha-glucosidase determines the type of GSD II an individual
129_76	may have. More alpha glucosidase present in the individual's muscles means symptoms occur later in
129_77	life and progress more slowly. GSD II is broadly divided into two onset forms based on the age
129_78	symptoms occur.
129_79	Infantile-onset form is usually diagnosed at 4–8 months; muscles appear normal but are limp and
129_80	weak preventing the child from lifting their head or rolling over. As the disease progresses, heart
129_81	muscles thicken and progressively fail. Without treatment, death usually occurs due to heart

128_202

See also Cowper and Newton Museum References Notes Citations Sources

128_203

. Preface by Haweis

128_204

(More legible (and machine-readable) transcription. For the facsimile edition at archive.org, see

128_205

below.)

128_206

Further reading

128_207

External links

128_208

Newton, John (1788). Thoughts Upon the African Slave Trade (Internet Archive with funding by

128_209

Associates of the Boston Public Library ed.). London: J. Buckland & J. Johnson. Retrieved 24 May

128_210

2019. (Facsimile of original book at Archive.org. For more legible (and machine-readable)

128_211

transcription, see Sources (above).)

128_212

The John Newton Project Biography & Articles on Newton

128_213

John Newton Papers Collection from the Digital Library of Georgia John Newton on Poeticous

128_214

1725 births 1807 deaths 18th-century English Anglican priests 18th-century Royal Navy personnel

128_215

19th-century English people English slave traders Calvinist and Reformed hymnwriters

128_216

Christian abolitionists Church of England hymnwriters Doctors of Divinity English abolitionists

128_217

English evangelicals Evangelical Anglicans Evangelical Anglican clergy

128_218

Evangelicalism in the Church of England People from Aveley People from Wapping Royal Navy officers

128_219

Royal Navy sailors Sailors from London

129_0

Glycogen storage disease type II, also called Pompe disease, is an autosomal recessive metabolic

129_1

disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation

129_2

of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. It is

129_3

the only glycogen storage disease with a defect in lysosomal metabolism, and the first glycogen

129_4

storage disease to be identified, in 1932 by the Dutch pathologist J. C. Pompe.

129_5

The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and

129_6

affects various body tissues, particularly in the heart, skeletal muscles, liver and the nervous

129_7

system.

129_8

Signs and symptoms Newborn

129_9

The infantile form usually comes to medical attention within the first few months of life. The

129_10

usual presenting features are cardiomegaly (92%), hypotonia (88%), cardiomyopathy (88%),

129_11

respiratory distress (78%), muscle weakness (63%), feeding difficulties (57%) and failure to thrive

129_12

(50%).

129_13

The main clinical findings include floppy baby appearance, delayed motor milestones and feeding

129_14

difficulties. Moderate hepatomegaly may or may not be present. Facial features include

129_15

macroglossia, wide open mouth, wide open eyes, nasal flaring (due to respiratory distress), and

129_16

poor facial muscle tone. Cardiopulmonary involvement is manifested by increased respiratory rate,

129_17

use of accessory muscles for respiration, recurrent chest infections, decreased air entry in the

129_18

left lower zone (due to cardiomegaly), arrhythmias and evidence of heart failure.

129_19

Prior to the development of a treatment, median age at death in untreated cases was 8.7 months,

129_20

usually due to cardiorespiratory failure, however this outcome is drastically changed since

129_21

treatment has been available, improving with early access to treatment.

129_22

Late onset form

129_23

This form differs from the infantile principally in the relative lack of cardiac involvement. The

129_24

onset is more insidious and has a slower progression. Cardiac involvement may occur but is milder

129_25

than in the infantile form. Skeletal involvement is more prominent with a predilection for the

129_26

lower limbs.

129_27

Late onset features include impaired cough, recurrent chest infections, hypotonia, progressive

129_28

muscle weakness, delayed motor milestones, difficulty swallowing or chewing and reduced vital

129_29

capacity.

129_30

Prognosis depends on the age of onset of symptoms with a better prognosis being associated with

129_31

later onset disease.

129_32

Cause

129_33

It has an autosomal recessive inheritance pattern. This means the defective gene is located on an

129_34

autosome, and two faulty copies of the gene — one from each parent — are required to be born with

129_35

the disorder. As with all cases of autosomal recessive inheritance, children have a 1 in 4 chance

129_36

of inheriting the disorder when both parents carry the defective gene, and although both parents

129_37

carry one copy of the defective gene, they are usually not affected by the disorder.

129_38

The disease is caused by a mutation in a gene (acid alpha-glucosidase: also known as acid maltase)

129_39

on long arm of chromosome 17 at 17q25.2-q25.3 (base pair 75,689,876 to 75,708,272). The number of

129_40

mutations described is currently (in 2010) 289 with 67 being non-pathogenic mutations and 197

129_41

pathogenic mutations. The remainder are still being evaluated for their association with disease.

129_42

The gene spans approximately 20 kb and contains 20 exons with the first exon being noncoding. The

129_43

coding sequence of the putative catalytic site domain is interrupted in the middle by an intron of

129_44

101 bp. The promoter has features characteristic of a 'housekeeping' gene. The GC content is high

129_45

(80%) and distinct TATA and CCAAT motifs are lacking.

129_46

Most cases appear to be due to three mutations. A transversion (T → G) mutation is the most common

129_47

among adults with this disorder. This mutation interrupts a site of RNA splicing.

129_48

The gene encodes a protein—acid alpha-glucosidase (EC 3.2.1.20)—which is a lysosomal hydrolase. The

129_49

protein is an enzyme that normally degrades the alpha -1,4 and alpha -1,6 linkages in glycogen,

129_50

maltose and isomaltose and is required for the degradation of 1–3% of cellular glycogen. The

129_51

deficiency of this enzyme results in the accumulation of structurally normal glycogen in lysosomes

129_52

and cytoplasm in affected individuals. Excessive glycogen storage within lysosomes may interrupt

129_53

normal functioning of other organelles and lead to cellular injury.

129_54

A putative homologue—acid alpha-glucosidase-related gene 1—has been identified in the nematode

129_55

Caenorhabditis elegans.

129_56

Diagnosis

129_57

In the early-onset form, an infant will present with poor feeding causing failure to thrive, or

129_58

with difficulty breathing. The usual initial investigations include chest X ray, electrocardiogram

129_59

and echocardiography. Typical findings are those of an enlarged heart with non specific conduction

129_60

defects. Biochemical investigations include serum creatine kinase (typically increased 10 fold)

129_61

with lesser elevations of the serum aldolase, aspartate transaminase, alanine transaminase and

129_62

lactic dehydrogenase. Diagnosis is made by estimating the acid alpha glucosidase activity in either

129_63

skin biopsy (fibroblasts), muscle biopsy (muscle cells) or in white blood cells. The choice of

129_64

sample depends on the facilities available at the diagnostic laboratory.

129_65

In the late-onset form, an adult will present with gradually progressive arm and leg weakness, with

129_66

worsening respiratory function. Electromyography may be used initially to distinguish Pompe from

129_67

other causes of limb weakness. The findings on biochemical tests are similar to those of the

129_68

infantile form, with the caveat that the creatine kinase may be normal in some cases. The diagnosis

129_69

is by estimation of the enzyme activity in a suitable sample.

129_70

On May 17, 2013 the Secretary's Discretionary Advisory Committee on Heritable Diseases in Newborns

129_71

and Children (DACHDNC) approved a recommendation to the Secretary of Health and Human Services to

129_72

add Pompe to the Recommended Uniform Screening Panel (RUSP). The HHS secretary must first approve

129_73

the recommendation before the disease is formally added to the panel.

129_74

Classification

129_75

There are exceptions, but levels of alpha-glucosidase determines the type of GSD II an individual

129_76

may have. More alpha glucosidase present in the individual's muscles means symptoms occur later in

129_77

life and progress more slowly. GSD II is broadly divided into two onset forms based on the age

129_78

symptoms occur.

129_79

Infantile-onset form is usually diagnosed at 4–8 months; muscles appear normal but are limp and

129_80

weak preventing the child from lifting their head or rolling over. As the disease progresses, heart

129_81

muscles thicken and progressively fail. Without treatment, death usually occurs due to heart